The longevity-associated BPIFB4 gene supports cardiac function and vascularization in ageing cardiomyopathy

Abstract

Aims The aging 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 the BPIFB4 gene enjoy prolonged health spans and lesser cardiovascular complications. Moreover, supplementation of LAV-BPIFB4 via an adeno-associated viral vector improves cardiovascular performance in limb ischemia, atherosclerosis, and diabetes models. Here, we asked if the LAV-BPIFB4 gene could address the unmet therapeutic need to delay the heart’s spontaneous aging. Methods and Results Immunohistological 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 homozygous LAV-BPIFB4 genotype. Moreover, pericytes isolated from older hearts showed low levels of BPIFB4, depressed pro-angiogenic activity, and loss of ribosome biogenesis. LAV-BPIFB4 supplementation restored pericyte function and pericyte-endothelial cell interactions through a mechanism involving the nucleolar protein nucleolin. Conversely, BPIFB4 silencing in normal pericytes mimed the heart failure pericytes. Finally, gene therapy with LAV-BPIFB4 prevented cardiac deterioration in middle-aged mice and rescued cardiac function and myocardial perfusion in older mice by improving microvasculature density and pericyte coverage. Conclusions We report the success of the LAV-BPIFB4 gene/protein in improving homeostatic processes in the heart’s aging. These findings open to using LAV-BPIFB4 to reverse the decline of heart performance in older people.

Effects of Human LAV-BPIFB4 Gene Therapy on the Epigenetic Clock and Health of Aged Mice

“…The “rejuvenating” properties of the LAV-BPIFB4 were demonstrated in pre-clinical models, with a broad spectrum of protective effects towards different pathological conditions, including inflammatory status [ 23 ], cardiovascular problems [ 21 ] and Huntington’s disease [ 27 ]. Interestingly, recent evidence demonstrated that LAV delivery caused a rejuvenation of the hearts of old mice by a human equivalent of more than ten years [ 22 ]. Here, we demonstrated that the LAV gene therapy was also able to slow down the epigenetic age progression in nucleated blood cells of aged mice.…”

“…Although such a reduction was more evident in males, female mice showed the same trend, and the absence of a significant difference may be likely due to the smaller sample size compared to the male one. In support of a sex-independent action of the LAV therapy, its effect on the cardiac function was clearly demonstrated in both male and female mice [ 22 ]. Nonetheless, a sex-specific activity was previously ascribed to the BPIFB4 protein, which inversely correlated with the severity of the COVID-19 disease in men but not in women [ 29 ].…”

“…The BPIFB4 protein, implicated in activating homeostatic processes such as adaptive stress response and proteostasis, is found at high levels in the serum of long-living people and the LAV-BPIFB4 genetic variant has been associated with healthy aging and exceptional longevity [ 19 ]. In addition, the LAV-BPIFB4 gene therapy in mouse models has been proven to rescue the age-related endothelial dysfunction [ 20 ], reduce the progression of cardiovascular diseases [ 21 ], delay heart aging [ 22 ], and decrease the pool of senescent cells and senescence-associated inflammation [ 23 , 24 ]. In such pre-clinical studies, the LAV-BPIFB4 gene was delivered through an adeno-associated virus (AAV serotype 9) carrying a liver-specific promoter.…”

“…In such pre-clinical studies, the LAV-BPIFB4 gene was delivered through an adeno-associated virus (AAV serotype 9) carrying a liver-specific promoter. Those studies demonstrated that the liver is the main target of AAV-LAV-BPIFB4 infection, which is also followed by (i) a rapid rise in the plasma level of the BPIFB4 protein [ 25 ], (ii) BPIFB4 enrichment in CD11b+ myeloid cells both in bone marrow and in blood without any mRNA upregulation (either human or murine), (iii) over-expression of the human protein in most tissues of transfected mice, such as the aorta and heart [ 22 , 25 , 26 ], and an increase in BPIFB4 in myocytes and vascular cells [ 22 ]. Collectively, previous data suggest that (i) the liver was transduced by the viral vector and (ii) the upregulation in vessels or immune cells of LAV-BPIFB4-treated mice was likely due to an uptake of circulating protein and not to an induction of the endogenous murine gene.…”

Role of noncoding RNAs in cardiac ageing

“…Thus, removal of senescent cells by senolytics improves the overall functioning of the heart, even in aged mice ( 77 , 83 ). In a recent study Cattaneo et al reported the importance of longevity-associated BPIFB4 ( LAV-BPIFB4 ) gene in supporting cardiac function and vascularization in ageing cardiomyopathy ( 84 ). They demonstrated reduced LAV-BPIFB4 in older hearts and that gene therapy with LAV-BPIFB4 rescued cardiac function and myocardial perfusion in aged mice by improving microvasculature density and pericyte coverage.…”