In aged mice, genetic clearance of p16-expressing senescent cells attenuated ventricular wall thickening and fibrosis and restored normal relaxation between beats
In aged mice, genetic clearance of p16-expressing senescent cells attenuated ventricular wall thickening and fibrosis and restored normal relaxation between beats
On September 14, Experimental Physiology published a paper from the Montreal Heart Institute: in INK-ATTAC mice, the drug AP20187 eliminated p16-expressing cells from 12 to 18 months of age. Over those six months, untreated animals developed progressive left ventricular wall thickening, myocardial fibrosis, and slower ventricular relaxation between beats; clearance of p16-positive cells attenuated all three changes.
A cell with active p16 is a senescent cell: it has stopped dividing but remains alive and secretes factors that damage the surrounding tissue. In the INK-ATTAC mouse line, these cells carry a genetic switch coupled to a fluorescent reporter: the drug AP20187 kills only the labeled cells, and the reporter then confirms precisely which cells were eliminated. This makes the system more specific than earlier pharmacological senolytics. With aging, the fraction of p16-positive cells increased across all cardiac cell types, most prominently in immune cells and in fibroblasts, the cells that build the heart's connective tissue.
Six months of AP20187 injections versus vehicle, and in treated mice left ventricular mass and wall thickness barely increased, while in controls both rose substantially. Isovolumic relaxation time (how quickly the heart relaxes and fills with blood between beats, measured by catheter) remained at young levels in treated mice but increased in controls. Ejection fraction (the proportion of blood the heart expels per beat) and contractile force were unchanged: the effect was selective for relaxation, not contraction.
Cell sorting and tissue-section staining showed that the drug reduced the fraction of p16-positive cells only among fibroblasts and cardiomyocytes; in vascular cells the fraction was unaffected. Alongside this reduction, expression of the hypertrophy gene Myh7 decreased and ventricular collagen content fell, confirmed both histologically and biochemically.
A separate in vitro experiment tested the mechanism: fibroblasts were driven into senescence with hydrogen peroxide and then co-cultured with healthy cardiomyocytes across a membrane permeable to soluble factors but not to cells. Within two days, the healthy muscle cells activated the same hypertrophic gene program, showing that senescent connective-tissue cells act on muscle cells at a distance through their secreted factors.
Cardiac muscle barely divides, and the heart poorly replaces lost cells. The authors themselves flag this as a theoretical risk of destroying senescent cardiomyocytes. The risk did not materialize: clearance was accompanied by cardiac improvement, not tissue loss. A similar outcome was seen with navitoclax after myocardial infarction in middle-aged mice: the scar occupied 13.6% of ventricular area versus 18.9% in controls. The experiments used males, and clearance was systemic.
The INK-ATTAC model comes from a 2016 study that linked accumulation of p16-positive cells to shortened healthspan in mice and became one of the foundational results in the science of cellular senescence. Earlier work from the same laboratory, led by senior author Stanley Bhatt Bhatt Nattel, focused on the atria and cardiac rhythm: a 2025 human trial already showed that the senolytic quercetin reduced the incidence of postoperative atrial fibrillation by more than 75%. The present paper extends the same logic to the ventricle and to relaxation between beats, that is, diastolic dysfunction, a common cause of heart failure in older people.