The Longevity-Associated Variant of BPIFB4 Reduces Heart Disease Severity

Few human longevity-associated gene variants are replicated in multiple patient populations. One of those is a variant of BPIFB4, that appears to improve immune function and lower inflammation by adjusting the behavior of macrophage cells of the innate immune system. Delivering the variant to mice using a gene therapy has similar effects. It may well operate via other mechanisms as well, however. Few proteins in a living cell turn out to have only one purpose.

In today's open access paper, researchers report that the BPIFB4 variant reduces the severity of coronary artery disease in humans and mice. Delivering the variant to heart tissue as a gene therapy improves outcomes in a mouse model of heart attack. While reduced inflammation should certainly help in the aftermath of a heart attack, and more broadly in the slow progression of heart disease, this outcome may result from a different mechanism to that involved in the modulation of immune function noted above. The gene therapy approach appears to affect heart cells directly, improving function and protecting against the stresses and damage resulting loss and restoration of blood supply following a heart attack.

BPIFB4 and its longevity-associated haplotype protect from cardiac ischemia in humans and mice

Unhealthy lifestyles and accrual of risk factors contribute to vascular dysfunction highlighted by cellular senescence and impaired synthesis and secretion of endothelium-derived vasoactive molecules. Genetic factors also participate in determining the dichotomy between cardiovascular health and disease. Nonetheless, very few gene polymorphisms proved to capture the divergence of cardiovascular clocks seen in high-risk individuals (HRIs) and long-living individuals (LLIs). Among them, the longevity variant (LAV) of the BPI Fold Containing Family B Member 4 (BPIFB4) gene, showed a preponderant impact on the cardiovascular system and prolonged life span, passing the validation of three geographically unrelated cohorts.

Carriers of the LAV-BPIFB4 gene express high levels of the encoded protein in the blood, circulating mononuclear cells, and vascular cells. Moreover, high levels of circulating BPIFB4 protein protected against carotid stenosis in human cohorts. Contrariwise, BPIFB4 is reportedly downregulated in the heart of patients with end-stage ischemic heart failure.

Importantly, we have provided substantial evidence for the possibility of transferring the healthy phenotype conferred by LAV-BPIFB4 to cardiovascular animal models, suggesting that temporary expression of an evolutionary successful human gene can halt and even reverse age-related damage. LAV-BPIFB4 gene therapy in mice demonstrated anti-atherosclerotic, anti-hypertensive, pro-angiogenic, and neuroprotective activities. Moreover, it improved frailty indices and diabetic and age-related cardiomyopathies, and rejuvenated the elderly vasculature. In addition, replicating the preserved immune function of centenarians, the LAV-BPIFB4 protein encouraged immunomodulatory responses by human myeloid cells.