A Model of Evolutionary Selection: The Cardiovascular Protective Function of the Longevity Associated Variant of BPIFB4

Abstract

Evolutionary forces select genetic variants that allow adaptation to environmental stresses. The genomes of centenarian populations could recapitulate the evolutionary adaptation model and reveal the secrets of disease resistance shown by these individuals. Indeed, longevity phenotype is supposed to have a genetic background able to survive or escape to age-related diseases. Among these, cardiovascular diseases (CVDs) are the most lethal and their major risk factor is aging and the associated frailty status. One example of genetic evolution revealed by the study of centenarians genome is the four missense Single Nucleotide Polymorphisms (SNPs) haplotype in bactericidal/permeability-increasing fold-containing family B, member 4 (BPIFB4) locus that is enriched in long living individuals: the longevity associated variant (LAV). Indeed, LAV-BPIFB4 is able to improve endothelial function and revascularization through the increase of endothelial nitric oxide synthase (eNOS) dependent nitric oxide production. This review recapitulates the beneficial effects of LAV-BPIFB4 and its therapeutic potential for the treatment of CVDs.

LAV-BPIFB4 associates with reduced frailty in humans and its transfer prevents frailty progression in old mice

“…Therefore, frailty reflects the individual’s biological age and life expectancy better than chronological age [3]. Studies in long-living individuals (LLIs), which, in spite of their exceptional biological age, are protected from and cope better with age-related diseases, confirm this concept [4]. Moreover, several genetic factors that are reportedly implicated in the determination of exceptional longevity are also inversely related with frailty disabilities [5, 6].…”

Transfer of a human gene variant associated with exceptional longevity improves cardiac function in obese type 2 diabetic mice through induction of the SDF‐1/CXCR4 signalling pathway

“…The liver-specific thyroxine-binding globulin (TBG) promoter was adopted for the AAV assembling. 6 As a confirmation, GFP fluorescence was detected in the liver (online supplementary Figure S4.A-F), but not in the heart (online supplementary Figure S4.G-J), of mice injected with the AAV-GFP vector. Using an antibody that recognises both the murine and human protein, we demonstrated that WT-BPIFB4 and LAV-BPIFB4 gene transfer induced similar increases in BPIFB4 staining in the heart, with specific localisation of the fluorescent signal in cardiomyocytes (P < 0.01 vs. vehicle; Figure 2B).…”

“…The prevalence of LAV homozygosity is 14% in centenarians and 10% in controls. 6 BPIFB4 is a secreted protein, its levels are increased in serum of long-living individuals, and high BPIFB4 levels classify their health status. 7 Likewise, homozygous LAV carriers have higher circulating BPIFB4 levels and increased phosphorylated endothelial nitric oxide synthase (eNOS) in circulating mononuclear cells.…”

New Insights for BPIFB4 in Cardiovascular Therapy

“…Indeed, centenarians’ children are more likely to reach extreme ages than their peers and show a decreased incidence of age-related pathologies [ 12 ]. Therefore, the world population of centenarians represents a very interesting genomic model and the analysis of the mechanisms that lead to longevity can be a great tool for understanding healthy aging [ 13 ].…”

“…Over the years, genetic analysis approaches, in particular GWAS (genome wide association study), have made possible the identification of genetic variants associated with longevity that confer an advantage in terms of survival [ 13 ].…”