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

Abstract

Background: There is an increasing concern about age-related frailty because of the growing number of elderly people in the general population. The Longevity-Associated Variant (LAV) of the human BPIFB4 gene was found to correct endothelial dysfunction, one of the mechanisms underlying frailty, in aging mice whereas the RV-BPIFB4 variant induced opposite effects. Thus, we newly hypothesize that, besides being associated with life expectancy, BPIFB4 polymorphisms can predict frailty.Aim and Results: Here we investigated if the BPIFB4 haplotypes, LAV, wild-type (WT) and RV, differentially associate with frailty in a cohort of 237 elderly subjects from Calabria region in Southern Italy. Moreover, we studied the effect of systemic adeno-associated viral vector-mediated LAV-BPIFB4 gene transfer on the progression of frailty in aging mice. We found an inverse correlation of the homozygous LAV-BPIFB4 haplotype with frailty in elderly subjects. Conversely, carriers of the RV-BPIFB4 haplotype showed an increase in the frailty status and risk of death. Moreover, in old mice, LAV-BPIFB4 gene transfer delayed frailty progression.Conclusions: These data indicate that specific BPIFB4 haplotypes could represent useful genetic markers of frailty. In addition, horizontal transfer of a healthy gene variant can attenuate frailty in aging organisms.

The Role of Oxidative Stress in Cardiovascular Aging and Cardiovascular Diseases

“…In line with these findings, circulating BPIFB4 levels were closely linked with the health status of long-living individuals [ 165 ]. Interestingly, LAV-BPIFB4 gene transfer decelerated frailty progression in aged mice and homozygous LAV-BPIFB4 haplotype inversely correlated with frailty in elderly subjects [ 166 ].…”

The longevity-associated variant of BPIFB4 improves a CXCR4-mediated striatum–microglia crosstalk preventing disease progression in a mouse model of Huntington’s disease

“…First, BPIFB4 has been shown to preserve cellular homeostasis through the activation of many heat shock protein (HSP) family members involved in maintaining and restoring favorable proteostatis 20,21 , which is progressively lost during aging and in neurodegenerative disease. Indeed LAV-BPIFB4 associates with reduced frailty in humans and its transfer prevents frailty progression in old mice 22 .…”

New Insights for BPIFB4 in Cardiovascular Therapy

“…At the time of recruitment, subjects resulted 51% non-frail and 49% frail. Subsequently, genotyping for BPIFB4 haplotypes has been performed and the association analysis showed that carriers for LAV-BPIFB4 homozygous are underrepresented in the frails, as opposed to RV-BPIFB4 haplotype which is more frequent in the frail subjects [ 37 ].…”

“…To validate the association of the BPIFB4 genotype with the fragile phenotype at a functional level, a further study was conducted on adult and elderly mice in which LAV-BPIFB4 was administered as gene therapy. Interestingly, attenuation of clinical frailty has been reported following treatment with LAV-BPIFB4 in elderly mice [ 37 ]. This work, for the first time, has associated clinical evidence with experimental results whereby a gene haplotype may influence frailty.…”