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• Research Paper Volume 9, Issue 2 pp 370-380

  The expression of the BPIFB4 and CXCR4 associates with sustained health in long-living individuals from Cilento-Italy

  Relevance score: 12.055687

  Gaia Spinetti, Elena Sangalli, Claudia Specchia, Francesco Villa, Chiara Spinelli, Rita Pipolo, Albino Carrizzo, Simona Greco, Christine Voellenkle, Carmine Vecchione, Paolo Madeddu, Fabio Martelli, Annibale Alessandro Puca

  Keywords: long-living individuals, mononuclear cell migration, BPIFB4, HIF-1α targets, CXCR4

  Published in Aging on January 22, 2017

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  The study of the health status in long-living individuals (LLIs) may help identifying health-span and life-span determinants. BPI-Fold-Containing-Family-B-Member-4 (BPIFB4) protein is higher in healthy vs. non-healthy (frail) LLIs serum and its longevity-associated variant forced expression improves cardiovascular outcomes in ischemia mice models. Thus, we tested the association of BPIFB4 and ischemia-responding HIF-1α pathway components (i.e. CXCR4, AK3, ALDO-C, ADM, VEGF-A, GLUT-1 and miR-210) with human life-span and health-span by analyzing mRNA expression in circulating mononuclear cells (MNCs) of LLIs (N=14 healthy; N=31 frail) and young controls (N=63).

  ALDO-C, ADM, VEGF-A and GLUT-1 significantly decreased and miR-210 increased in LLIs vs. controls. Only VEGF-A and GLUT-1 showed further significant reduction in healthy-LLIs vs. frail-LLIs comparison. While BPIFB4 and CXCR4 were similar between LLIs and controls, BPIFB4 was significantly higher and CXCR4 lower in healthy- versus frail-LLIs. On a new set of LLIs (N=7 healthy and N=5 non-healthy) we assessed a potentially correlated function with low CXCR4 expression. Healthy donors' MNCs showed efficient migration ability toward CXCR4 ligand SDF-1α/CXCL12 and high percentage of migrated CXCR4^pos cells which inversely correlated with CXCR4 RNA expression. In conclusion, BPIFB4 and CXCR4 expression classify LLIs health status that correlates with maintained MNCs migration.

  

  Circulating MNCs of long living individuals (LLIs) show similar BPIFB4 gene levels but modulation in HIF-1α hallmark factors compared to young controls. Box plots of the mRNA levels (log2 scale) of BPIFB4 and HIF-1α-associated factors (CXCR4, ALDO-C, ADM, miR-210, VEGF-A, GLUT-1, AK3) in LLIs (N=45) versus controls (N=63).

  
  
  

  

  Effect of disease on the mRNA signature. The LLI group was subdivided based on the presence/absence of age-associated diseases. Next, the RNA levels in MNC of the indicated genes was measured in healthy (N=14) vs. non-healthy (N=31) donors. Data are shown as box plots in a log2 scale.

  
  
  

  

  Migratory ability of LLI MNCs is impaired in non-healthy donors and associates with percentage of membrane CXCR4-positive cells. (A) Dot plot showing results of in vitro migration assay performed on a separate group of healthy (N=7) and non-healthy (N=5) LLIs. Number of MNCs migrated in the lower chamber toward vehicle (migration medium containing 0.1% serum bovine albumin, BSA) or chemoattractant SDF-1α (CXCL12) is shown. (B) Percentage of CXCR4 (SDF-1α receptor)-positive MNCs was measured by flow cytometry in migrated (MIG) and not migrated (NOT MIG) harvested from the upper and lower chamber of the migration system respectively. Results of the 12 donors are shown in the dot plot.

  
  
  

  

  Migratory ability of LLI MNCs is impaired in non-healthy donors and associates with percentage of membrane CXCR4-positive cells. (C) Representative flow cytometry plot showing CXCR4^pos MNCs in migrated and not migrated fractions. Negative control (Neg CTRL) indicates not stained MNCs. (D-F) Association analysis of SDF-1α-migrated MNCs and percentage of CXCR4^pos cells (P=0.04), percentage of CXCR4^pos cells and CXCR4 relative expression (P=0.04), and SDF-1α-migrated MNCs and CXCR4 relative expression (P=0.06).