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The heart begins to age from the moment of birth. A new study using the largest cardiac gene map ever assembled has confirmed that this aging is not simply the passage of time — it is a precise sequence of events in which specific genes switch off and on inside heart cells.

Particularly striking was the finding that replenishing a key gene whose activity declines with age in the hearts of old mice actually restored cardiac function.

A joint research team led by professor Jiangping Song of Fuwai Hospital in China and professor Daniel Reichart of Ludwig Maximilian University of Munich in Germany analyzed gene activity in 442,239 cell nuclei from 54 cardiac tissue samples taken from 29 individuals ranging from fetal stage to age 75. Their findings, published in volume 12, issue 25 of the international journal Science Advances, tracked how the heart changes at the cellular level across an entire lifetime.

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Hearts fill with inflammation as they age

The analysis revealed a common pattern of change across all major cell types in the heart. With advancing age, the balance of cellular function broke down, and inflammation signals and stress responses increased.

The changes were most pronounced in cardiac muscle cells. Cell types abundant in youth gradually declined with age, while specific cell populations associated with aging came to dominate hearts in people over 60.

Compared with cardiac tissue from a 53-year-old (left), tissue from a 73-year-old (right) shows a sharp increase in a specific protein linked to cellular aging and stress — CRYAB, shown in red — spreading across the entire heart. [Science Advances, Vol. 12, No. 25]
Compared with cardiac tissue from a 53-year-old (left), tissue from a 73-year-old (right) shows a sharp increase in a specific protein linked to cellular aging and stress — CRYAB, shown in red — spreading across the entire heart. [Science Advances, Vol. 12, No. 25]

These cells displayed characteristics of stress-worn tissue and showed considerable overlap with genes associated with heart diseases such as dilated cardiomyopathy, a condition in which the heart abnormally enlarges.

The same pattern — rising activity of inflammation-related genes with age — appeared in non-muscle cardiac cells as well, including vascular cells and connective tissue cells.

The research team said cardiac aging is not a problem confined to any single cell type but a change that spans the entire heart.

A single gene drives heart cell aging

Microscope images showing cardiac muscle cells stained for aging markers after the key gene was suppressed (bottom). Unlike the control group (top), a significant portion of the cells turned deep blue — the marker for senescent cells. The images demonstrate that switching off a single gene was enough to cause rapid aging in heart cells. [Science Advances, Vol. 12, No. 25]
Microscope images showing cardiac muscle cells stained for aging markers after the key gene was suppressed (bottom). Unlike the control group (top), a significant portion of the cells turned deep blue — the marker for senescent cells. The images demonstrate that switching off a single gene was enough to cause rapid aging in heart cells. [Science Advances, Vol. 12, No. 25]

The research team analyzed regulatory factors whose activity declines with age.

Among them, a gene called PRDM16 showed the most consistent and pronounced decrease with aging. Protein levels of PRDM16 were also lower in hearts from people over 60 than in those from young adults.

To directly test its function, the team suppressed the gene in cardiac muscle cells derived from human stem cells. The results were clear.

Images of human cardiac muscle cells with the key gene PRDM16 functioning normally (top) and artificially suppressed (bottom). When the gene was blocked, the cardiac muscle cells grew abnormally large, displaying signs of cardiac hypertrophy. [Science Advances, Vol. 12, No. 25]
Images of human cardiac muscle cells with the key gene PRDM16 functioning normally (top) and artificially suppressed (bottom). When the gene was blocked, the cardiac muscle cells grew abnormally large, displaying signs of cardiac hypertrophy. [Science Advances, Vol. 12, No. 25]

Proteins that inhibit cell division increased, cells grew larger, and the organelles responsible for energy production lost function. Secretion of inflammatory substances also rose. The loss of a single gene was enough to make cardiac muscle cells begin behaving like aged cells.

When the team restored the gene in the hearts of old mice, the outcome changed. The hearts' ability to pump blood improved significantly compared with the control group, abnormally enlarged cells shrank, and several cellular functions that had deteriorated with age were partially restored.

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Team also develops clock to measure heart age

Drawing on the data gathered in the study, the research team also developed a model that predicts the biological age of the heart using gene activity patterns alone. The model proved highly accurate, matching actual age 99 percent of the time.

When applied to patients with heart disease, the model produced a notable result: the predicted heart age came out higher than the patients' actual age. This suggests that a diseased heart ages faster at the genetic level than its chronological age would indicate.

The team noted, however, that the study focused primarily on healthy hearts and did not systematically analyze differences by sex. They added that further research is needed to determine whether the decline of PRDM16 is a cause or a consequence of cardiac aging.

Reference

DOI: 10.1126/sciadv.aeg2614

Hao Jia et al., "Life-span-dependent transcriptional dynamics of the human heart," Science Advances 12, eaeg2614 (2026).


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