Spatial evidence of senescence-associated pathology after myocardial infarction in humans and therapeutic targeting in ageing mice
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Myocardial infarction predominantly affects older adults, yet whether post-injury senolysis improves repair in a middle-aged heart, and whether senescence-associated pathology is present in human post-infarction myocardium, remain unclear. We treated 15-month-old male mice, an age-relevant middle-aged model, with navitoclax for seven days after ischaemia–reperfusion injury. Navitoclax reduced p16INK4a-positive and p21CIP1-positive nuclei and was associated with smaller scars, reduced immune-cell accumulation, increased peri-infarct vascularisation and attenuated cardiomyocyte hypertrophy. We also analysed spatial-transcriptomic data from human post-infarction myocardium. Infarct-zone tissue showed increased CDKN2A-positive spot frequency and broader senescence-associated transcriptional activity. Senescence-high niches were enriched for fibrotic and inflammatory programmes, showed altered inferred immune composition and had increased detection of anti-apoptotic BCL-2-family transcripts, including navitoclax targets. To our knowledge, this is the first spatial, multi-gene evidence of a broader senescence-associated programme in pathologically defined human post-infarction myocardium. Together, these findings show that post-injury navitoclax improves histological remodelling in middle-aged mice and support cellular senescence as a candidate therapeutic target after myocardial infarction.
