Scientists have long known that aging drives inflammation in the heart, but exactly how those changes are distributed throughout the organ has remained unclear. Now, a team from The Jackson Laboratory (JAX) has pinpointed hotspots where these "inflammaging" signals concentrate, providing a new map of cardiac aging and a foundation for future studies of cardiovascular health and decline.
In a study of mouse hearts published today in Aging Cell, JAX researchers found that cellular signatures associated with age-related inflammation and scarring concentrated in the aortic valves and aortic root, where immune and connective tissue cells interact in ways that change with age and may influence the health of the surrounding heart muscle.
"Some of the markers associated with inflammaging were there from the very beginning in young hearts, but they were focused specifically in areas no one had defined before, in the valves and the aorta rather than in muscle tissue," said study author Nadia Rosenthal , scientific director at JAX. "We really have to think of aging as something that is not linear, because just like we know that people don't age at the same rate, what we know now is that organs and tissues don't age at the same rate either, even within one individual."
Previous studies have often focused on the heart's muscle cells, especially the left ventricle, because it's the main pumping chamber that sends blood through the aorta to the body. By examining the whole heart rather than focusing mainly on its muscle, the JAX team revealed a more nuanced picture of how cardiac cells and their molecular interactions change with age.
"The valves and the major blood vessels are parts often thought of as plumbing rather than the main engine, but this is a very complicated little machine," Rosenthal said. "It turns out they're home to many of the cells we're interested in, and that's where some of the most important aging-related signals were concentrated."
A new map of the aging heart
Age is the main risk factor for cardiovascular disease, but scientists don't fully understand how it alters heart tissue at the cellular level. One reason is that heart muscle cells in mammals are largely incapable of self-renewal and replacement. To investigate these age-related changes, Rosenthal's lab examined thousands of cells from young and aged mouse hearts with a combination of single-cell and spatial genomics technologies.
Previous research has shown that aging is accompanied by low-grade, chronic inflammation. Studies of the heart have also documented this shift and reported increases in immune cells that help coordinate inflammatory responses (macrophages) and structural cells that maintain connective tissue and form scars (fibroblasts).
Building on that work, the researchers found that macrophages showed increased activity in genes linked to inflammation and tissue remodeling, while fibroblasts became more likely to exhibit patterns associated with fibrosis (or scarring). But the team didn't just identify age-related genes in different cells. They also pinpointed where those cells were located within the heart, mapping in detail how individual cells and tissues appear to change with age.
Rather than finding signs of aging evenly distributed, the researchers discovered hotspots of inflammation and fibrosis (or scarring) concentrated in the valves and aortic root. They concluded that these regions may serve as hubs of cardiac aging, where inflammation and aging signals concentrate, potentially influencing surrounding muscle tissue.
"To keep muscle cells happy, the other cells in the heart have to continue supporting them throughout life," Rosenthal said. "What this study does, for the first time, is provide a comprehensive picture of how those support cells, particularly fibroblasts and macrophages, change with age and contribute to what we call inflammaging."
One surprising finding involved molecular markers commonly used to identify senescent, or aging, cells. Senescence occurs when cells permanently stop dividing, often in response to stress or aging. Their accumulation can contribute to chronic inflammation, tissue damage and age-related disease.
"What surprised us was that some of these markers that have been associated with aging were already present in young hearts. They weren't where anyone expected to find them, and that forced us to rethink what those markers are telling us," Rosenthal said. "That turns the usual interpretation of cardiac aging on its ear because these markers alone don't mean a cell is senescent. There's nothing senescent about a six-month-old mouse heart."
An entire conversation that changes with age
The study also identified genes whose activity increased with age and was concentrated in the same regions. Two genes stood out: Ccl8, an inflammatory signaling molecule, and Cdkn1a (also known as p21), a widely recognized marker of cellular senescence. Together, the findings reinforce evidence that the valves and aortic root may function as localized hubs of cardiac aging.
"We're not talking about single genes. We're talking about an entire conversation between immune cells and fibroblasts. As the heart ages, the way those cells communicate changes, and that shift appears to be linked to the inflammation and tissue remodeling we see in older hearts," Rosenthal said.
Just as aging-related changes were not distributed evenly throughout the heart, they were not identical between the sexes. In males, aging fibroblasts were associated with molecular pathways often linked to fibrosis. In females, aging fibroblasts were linked to pathways related to heart development and protein production. The findings mirror what happens in humans, where cardiovascular disease tends to increase after menopause in females but develops more gradually in males, Rosenthal said, suggesting these cellular changes may be relevant to known differences in cardiovascular aging between males and females.
While those are molecular differences, not changes in heart function or disease risk, the findings may help explain known aspects of cardiovascular aging in humans. By comparing the results with previously published human heart data, the researchers found that several age-related molecular programs, including stress-response pathways, were shared between mice and humans.
"Our findings change the focus from aging across the entire heart to specific anatomical hotspots, helping us better understand how inflammation and fibrosis are connected and which regions of the heart are involved in the aging process," said study author Amalia Sintou , a postdoctoral associate at JAX.
The study doesn't immediately point to new therapies. However, it provides scientists with a detailed map of where aging-related changes occur in the heart and which cells may be involved. These data could be the basis for future research aimed at slowing cardiovascular decline, preserving heart function, and promoting healthier aging, Rosenthal said.
Her team is now investigating how factors such as exercise, diet and disease may influence these cellular interactions. The goal is to understand what changes during normal aging that might make the heart more susceptible to disease later in life.
"Valve replacement is common in older adults, and one of the big questions is how much of the underlying damage is driven by aging itself," said study author Aleksandra Aljakna Khan , a postdoctoral associate at JAX. "Because all of the mice in our study lived in the same environment and ate the same diet, we were able to isolate the effects of aging and show that aging alone can initiate some of these changes in the valves and aorta."
This work was supported by the NIH Common Fund through The Jackson Laboratory Senescence Tissue Mapping Center (JAX-Sen TMC U54 AG079753), with additional support from JAX's National Cancer Institute-designated Cancer Center (P30 CA034196).
Other authors of the study were Yue Zhao, Antonios Somarakis, Harshpreet Chandok, Juliana Alcoforado Diniz, Ramalakshmi Ramasamy, Gretchen T. Clark, Brian S. White, Paul Robson, Ron Korstanje, and J. Matthew Mahoney of The Jackson Laboratory; and Leon Frommer and Sikander Hayat of RWTH Aachen University.
