AbstractAimsThe ageing heart naturally incurs a progressive decline in function and perfusion that available treatments cannot halt. However, some exceptional individuals maintain good health until the very late stage of their life due to favourable gene–environment interaction. We have previously shown that carriers of a longevity-associated variant (LAV) of theBPIFB4gene enjoy prolonged health spans and lesser cardiovascular complications. Moreover, supplementation ofLAV-BPIFB4 viaan adeno-associated viral vector improves cardiovascular performance in limb ischaemia, atherosclerosis, and diabetes models. Here, we asked whether theLAV-BPIFB4gene could address the unmet therapeutic need to delay the heart’s spontaneous ageing.Methods and resultsImmunohistological studies showed a remarkable reduction in vessel coverage by pericytes in failing hearts explanted from elderly patients. This defect was attenuated in patients carrying the homozygousLAV-BPIFB4genotype. Moreover, pericytes isolated from older hearts showed low levels of BPIFB4, depressed pro-angiogenic activity, and loss of ribosome biogenesis.LAV-BPIFB4supplementation restored pericyte function and pericyte-endothelial cell interactions through a mechanism involving the nucleolar protein nucleolin. Conversely,BPIFB4silencing in normal pericytes mimed the heart failure pericytes. Finally, gene therapy withLAV-BPIFB4prevented cardiac deterioration in middle-aged mice and rescued cardiac function and myocardial perfusion in older mice by improving microvasculature density and pericyte coverage.ConclusionsWe report the success of the LAV-BPIFB4 gene/protein in improving homeostatic processes in the heart’s ageing. These findings open to using LAV-BPIFB4 to reverse the decline of heart performance in older people.