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

Marco Malavolta,Francesco De Rango,Paolo Madeddu,Giuseppe Passarino,Carmine Vecchione,Fiorenza Orlando,Francesca Iannone,Anna Maciag,Francesco Villa,Annibale A Puca,Mauro Provinciali,Andrea Basso,Albino Carrizzo,Antonio D'Amato,Giuseppina Rose,Elena Ciaglia,Anna Ferrario,Serena Dato

doi:10.18632/aging.102209

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.

Highlights

Frailty is a clinically recognizable state of increased vulnerability to stressor events resulting from the systemic decline in function and physiological reserve mechanisms with aging [1]
In old mice, Longevity-Associated Variant (LAV)-BPIFB4 gene transfer delayed frailty progression. These data indicate that specific BPIFB4 haplotypes could represent useful genetic markers of frailty
The association analyses with frailty trait showed that the LAV homozygous haplotype is under-represented in frail subsets of the cohort (p = 0.030 vs. other haplotypes), suggesting a potentially protective role of this variant (Table 2 and Figure 1)

Summary

Introduction

Frailty is a clinically recognizable state of increased vulnerability to stressor events resulting from the systemic decline in function and physiological reserve mechanisms with aging [1]. This weakening condition detrimentally affects the normal physical activity and is associated with an increased risk for adverse clinical outcomes and death [2]. We found a consistent enrichment of the minor allele of the nonsynonymous single nucleotide polymorphism (SNP) rs2070325 of BPIFB4 (identifier: P59827.2), under recessive model, in LLIs. The rs2070325 is part of a four SNPs haplotype that codifies for a wild type variant (WT), a longevity-associated variant (LAV) and a rare variant (RV) of BPIFB4, represented respectively by the 66%, the 29.5% and the 4% of the alleles [7]. We newly hypothesize that, besides being associated with life expectancy, BPIFB4 polymorphisms can predict frailty

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