A research team has recently investigated a role for BPIFB4 in human longevity. They have identified a variant of this gene that appears more often in a population of long-lived individuals than in other people. They have also investigated how this gene might influence aging; the present view is that it acts to make a larger fraction of monocytes and macrophages adopt the M2 anti-inflammatory phenotype than would otherwise be the case. Chronic inflammation is highly influential in the progression of aging and age-related disease, and thus we should probably expect long-lived individuals to exhibit better control of inflammation to at least some degree.
In industrialized countries, lifespan averages 78 for males and 83 for females, but some exceptional individuals delay aging and live much longer than the rest of the population. Long Living Individuals (LLIs) represent a model of positive biology. We posit that the peripheral blood of LLIs may hold valuable biomarkers associated with an enduring performance of the immune system. Circulating factors unique to LLIs may also be directly involved in maintaining a proper balance between M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophage phenotypes.
The bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) is one of the most abundant proteins in respiratory secretions. BPIFB4 expression is highly responsive to airborne pathogens and participates in host protection. Of note, circulating BPIFB4 levels are constitutively increased in healthy LLIs as compared to frail ones and young controls. Moreover, carriers of the longevity-associated variant (LAV) have extremely prolonged life expectancy and show higher circulating BPIFB4 levels as compared with carrier of the wild-type haplotype.
We hypothesize that BPIFB4 may influence monocytes pool and macrophages skewing, shifting the balance toward an anti-inflammatory phenotype. We profiled circulating monocytes in 52 LLIs (median-age 97) and 52 healthy volunteers (median-age 55). If the frequency of total monocyte did not change, the intermediate CD14++CD16+ monocytes counts were lower in LLIs compared to control adults. Conversely, non-classical CD14+CD16++ monocyte counts, which are M2 macrophage precursors with an immunomodulatory function, were found significantly associated with the LLIs' state.
In a differentiation assay, supplementation of the LLIs' plasma enhanced the capacity of monocytes, either from LLIs or controls, to acquire a paracrine M2 phenotype. A neutralizing antibody against BPIFB4 blunted the M2 skewing effect of the LLIs' plasma. This data indicates that LLIs carry a peculiar anti-inflammatory myeloid profile, which is associated with and possibly sustained by high circulating levels of BPIFB4. Supplementation of recombinant BPIFB4 may represent a novel means to attenuate inflammation-related conditions typical of unhealthy aging.