From Longevity Wiki

BPIFB4 (Bactericidal/permeability-increasing fold-containing family B member 4), formerly known as LPLUNC4, is a secreted protein that in humans is encoded by the BPIFB4 gene located on chromosome 20.[1] The BPIFB4 consists of 614 amino acids and has a molecular weight of 65,055 Da. It belongs to the BPI (bactericidal/permeability-increasing protein) fold-containing superfamily, which are defined as proteins that contain domains of the BPI fold and known as antibacterial components that participates in host protection through antimicrobial, surfactant, and immunomodulatory properties.[2][1] Domains of the BPI fold are pockets in the protein structure capable of binding lipids and especially phosphatidylcholine[3]

BPIFB4 was originally found in the salivary glands, but was later found to play an important pathophysiological role. at the system level and is also expressed in the olfactory epithelium, mononuclear cells, germline, stem cells, progenitor cells and fetal cells.

LAV — longevity-associated variant of BPIFB4

Genome-wide association search (GWAS) of long-living individuals has shown that certain BPIFB4 variants are associated with exceptional longevity, in particular a variant containing four missense mutations (Val229/Thr281/Phe488/Thr494-BPIFB4) nucleotide polymorphism with an allele frequency in the European population of 29.5% called LAV (longevity-associated variant) wherein LAV homozygous genotype reaches 14% in centenarians.[4][5]

The most common variant (Ile229/Asn281/Leu488/Ile494-BPIFB4), called wild-type-WT-BPIFB4, found in 66% of population, while the Rare Variant (Ile229/Asn281/Phe488/Thr494-BPIFB4) does not exceed 4% of the population.[4] Humans carriers of RV-BPIFB4 had significantly increased blood pressure and exposure of ex-vivo human vessels to a human recombinant RV-BPIFB4 protein negatively modulated endothelial function and eNOS activation.[6] Furthermore, forced expression of RV-BPIFB4 in WT mice by dint of injected RV-BPIFB4-encoding AAV vector, evoked vascular eNOS dysfunction and increased basal systolic blood pressure to a degree similar to that seen in eNOS-deficient mice.[6]

WT-BPIFB4 and LAV-BPIFB4 have different subcellular localization. In particular WT-BPIFB4 shows a nuclear localization, while LAV-BPIFB4 is mostly cytoplasmic[4] due to its ability to be activated by phosphorylation at Ser75 of BPIFB4, which induces its complexation with cytoplasmic membranes14-3-3 proteins, which are capable of modulation of signaling pathways leading to transcriptional changes, apoptosis, autophagy, endoplasmic reticulum stress, cell cycle regulation, mitochondrial function and excitation–contraction coupling in smooth muscle.[7]

The BPIFB4/14-3-3 complex can recruit heat shock protein 90 kDa (Hsp90), to induce eNOS phosphorylation in Ser1177 resulting in NO production in endothelial cells.[8][9] Moreover, LAV-BPIFB4 is phosphorylated by protein kinase C alpha (PKCα) in Ser75, which activates calcium mobilization, which in turn determines PKCα activation, generating a feed-forward mechanism. [8]

Healthily aged long-living individuals have significantly higher serum BPIFB4 than do frail individuals.[10] BPIFB4 mRNA levels are also elevated in the total circulating mononuclear cells fraction from healthy long-living individuals as compared with non-healthy frail individuals.[11] Moreover, gene therapy by systemic adeno-associated viral vector-mediated LAV-BPIFB4 gene transfer counteracted the development of vascular atherosclerosis in ApoE knockout mice fed a high fat diet, that makes LAV-BPIFB4 a suitable candidate tool for the treatment of atherosclerosis and its related CVD complications.[12] Furthermore, LAV-BPIFB4 gene therapy caused a temporary reduction in systolic blood pressure in diabetic and non-diabetic aged mice, with pressure values returning to baseline by day 6 until the end of the study, albeit the benefit on endothelial-mediated vasorelaxation persisted up to a month after treatment.[13] In old mice LAV-BPIFB4 gene transfer delayed frailty progression.[10]

Therapeutic effects of LAV-BPIFB4 may be due to its regulation of calcium via CXCL12 chemokine receptor CXCR4-SDF1 pathway.[12][13] LAV-BPIFB4 exerted an anti-inflammatory and pro-resolving macrophage M2-polarizing effect via CXCR4-dependent mechanism and a reduction in T-cell activation.[12][14]

LAV-BPIFB4 activity maybe also preventing the aging-specific disruption of NAD+ homeostasis by means of the reduction of upbuilding CD38+ inflammatory cells that generally accumulate in tissues during chronological aging and actively destroy NAD+.[15] Long-living-individuals LAV-carriers, were characterized by high NAD+ levels.[15]


  1. 1.0 1.1 Bingle, C. D., & Gorr, S. U. (2004). Host defense in oral and airway epithelia: chromosome 20 contributes a new protein family. The international journal of biochemistry & cell biology, 36(11), 2144-2152. PMID: 15313462 DOI: 10.1016/j.biocel.2004.05.002
  2. Bingle, C. D., Seal, R. L., & Craven, C. J. (2011). Systematic nomenclature for the PLUNC/PSP/BSP30/SMGB proteins as a subfamily of the BPI fold-containing superfamily. PMC3196848 DOI: 10.1042/BST0390977
  3. Bülow, S., Zeller, L., Werner, M., Toelge, M., Holzinger, J., Entzian, C., ... & Gessner, A. (2018). Bactericidal/permeability-increasing protein is an enhancer of bacterial lipoprotein recognition. Frontiers in immunology, 9, 2768. PMID: 30581431 PMC6293271 DOI: 10.3389/fimmu.2018.02768
  4. 4.0 4.1 4.2 Villa, F., Carrizzo, A., Spinelli, C. C., Ferrario, A., Malovini, A., Maciąg, A., ... & Puca, A. A. (2015). Genetic analysis reveals a longevity-associated protein modulating endothelial function and angiogenesis. Circulation research, 117(4), 333-345. Circ Res; 117(4): 333–345. PMC: 5496930 doi :10.1161/CIRCRESAHA.117.305875
  5. Spinelli, C. C. (2014). La Variante Associata alla Longevità (LAV) del gene BPIFB4 modula eNOS e la funzionalità vascolare. TESI DI DOTTORATO DI RICERCA. TUTORE: Prof. S. BOSARI; CO-TUTORE: Dott. A. PUCA.
  6. 6.0 6.1 Vecchione, C., Villa, F., Carrizzo, A., Spinelli, C. C., Damato, A., Ambrosio, M., ... & Puca, A. A. (2017). A rare genetic variant of BPIFB4 predisposes to high blood pressure via impairment of nitric oxide signaling. Scientific reports, 7(1), PMC5574984 DOI:10.1038/s41598-017-10341-x
  7. Thompson, W. C., & Goldspink, P. H. (2022). 14–3-3 protein regulation of excitation–contraction coupling. Pflügers Archiv-European Journal of Physiology, 474(3): 267–279. PMID: 34820713 PMC8837530 DOI: 10.1007/s00424-021-02635-x
  8. 8.0 8.1 Spinelli, C. C., Carrizzo, A., Ferrario, A., Villa, F., Damato, A., Ambrosio, M., ... & Vecchione, C. (2017). LAV-BPIFB4 isoform modulates eNOS signalling through Ca2+/PKC-alpha-dependent mechanism. Cardiovascular Research, 113(7), 795-804. PMID: 28419216 PMC5437365 DOI:10.1093/cvr/cvx072
  9. Kraehling, J. R., & Sessa, W. C. (2015). Enhanced eNOS activation as the fountain of youth for vascular disease: is BPIFB4 what ponce de leon was looking for?. Circulation research, 117(4), 309-310. PMID: 26227874 PMC: PMC4676071 DOI: 10.1161/CIRCRESAHA.115.307020
  10. 10.0 10.1 Malavolta, M., Dato, S., Villa, F., De Rango, F., Iannone, F., Ferrario, A., ... & Puca, A. A. (2019). LAV-BPIFB4 associates with reduced frailty in humans and its transfer prevents frailty progression in old mice. Aging (Albany NY), 11(16), 6555. PMID: 31461407 PMC6738439 DOI:10.18632/aging.102209
  11. Spinetti, G., Sangalli, E., Specchia, C., Villa, F., Spinelli, C., Pipolo, R., ... & Puca, A. A. (2017). The expression of the BPIFB4 and CXCR4 associates with sustained health in long-living individuals from Cilento-Italy. Aging (Albany NY), 9(2), 370. PMID: 28121621 PMC5361669 DOI:10.18632/aging.10115
  12. 12.0 12.1 12.2 Puca, A. A., Carrizzo, A., Spinelli, C., Damato, A., Ambrosio, M., Villa, F., ... & Vecchione, C. (2020). Single systemic transfer of a human gene associated with exceptional longevity halts the progression of atherosclerosis and inflammation in ApoE knockout mice through a CXCR4-mediated mechanism. European Heart Journal, 41(26), 2487-2497. PMID: 31289820 PMC7340354 DOI: 10.1093/eurheartj/ehz459
  13. 13.0 13.1 Dang, Z., Avolio, E., Thomas, A. C., Faulkner, A., Beltrami, A. P., Cervellin, C., ... & Madeddu, P. (2020). 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. European journal of heart failure, 22(9), 1568-1581. PMC8220375 doi:10.1002/ejhf.1840
  14. Di Pardo, A., Ciaglia, E., Cattaneo, M., Maciag, A., Montella, F., Lopardo, V., ... & Puca, A. A. (2020). The longevity-associated variant of BPIFB4 improves a CXCR4-mediated striatum–microglia crosstalk preventing disease progression in a mouse model of Huntington’s disease. Cell death & disease, 11(7), 1-16. PMID: 32683420 PMC7368858 DOI:10.1038/s41419-020-02754-w
  15. 15.0 15.1 Ciaglia, E., Lopardo, V., Montella, F., Carrizzo, A., Di Pietro, P., Malavolta, M., ... & Puca, A. A. (2022). Transfer of the longevity-associated variant of BPIFB4 gene rejuvenates immune system and vasculature by a reduction of CD38+ macrophages and NAD+ decline. Cell death & disease, 13(1), Article number: 86. PMID: 35087020 PMC8792139 DOI:10.1038/s41419-022-04535-z

For further information

  • Montella, F., Lopardo, V., Cattaneo, M., Carrizzo, A., Vecchione, C., Puca, A. A., & Ciaglia, E. (2022). Role of BPIFB4 in Immune System and Cardiovascular Disease: The Lesson from Centenarians. Transl. Med. UniSa, 24(1), Article 2. https://doi.org/10.37825/2239-9747.1024
  • Lopardo, V., Conti, V., Montella, F., Iannaccone, T., Esposito, R. M., Sellitto, C., ... & Ciaglia, E. (2022). Gender Differences Associated with the Prognostic Value of BPIFB4 in COVID-19 Patients: A Single-Center Preliminary Study. Journal of personalized medicine, 12(7), 1058. https://doi.org/10.3390/jpm12071058
  • Ciaglia, E., Lopardo, V., Montella, F., Sellitto, C., Manzo, V., De Bellis, E., ... & Puca, A. A. (2021). BPIFB4 circulating levels and its prognostic relevance in COVID-19. The Journals of Gerontology: Series A, 76(10), 1775-1783.
  • Puca, A. A., Lopardo, V., Montella, F., Di Pietro, P., Cesselli, D., Rolle, I. G., ... & Ciaglia, E. (2022). The Longevity-Associated Variant of BPIFB4 Reduces Senescence in Glioma Cells and in Patients’ Lymphocytes Favoring Chemotherapy Efficacy. Cells, 11(2), 294. https://doi.org/10.3390/cells11020294