Many drugs have their origin in a human gene variant or mutation that was discovered to be protective in some way. Typically such drugs are less effective than possessing the mutation, for all the usual reasons. A drug is only used for some years rather than the whole lifespan, doesn't give the 100% coverage of cells in a tissue that the mutation does, and usually only recreates a fraction of the effects of the mutation in any given cell. Thus mutations that lower circulating LDL-cholesterol in the bloodstream can produce as much as a 50% reduction in lifetime risk of cardiovascular mortality, but drugs that reduce LDL-cholesterol levels produce only a 10-20% reduction, depending on which studies one chooses to take as representative.
Nonetheless, the discovery of protective mutations and gene variants is a sizable concern continues to lead to drug development programs. Today's open access paper reviews the mechanisms by which a longevity-associated variant of BPIFB4 is thought to lower risk of mortality. It appears to act in two ways, firstly by improving vascular function in older people, and secondly by reducing inflammation. The effects on vascular function are complex, involving reduced stiffening of vessels due to smooth muscle dysfunction, increased formation of new vessels, and increased antioxidant activity to reduce oxidative stress. As is usually the case, it is unclear as to which of these mechanisms is most important in determining the observed outcome of reduced late life mortality; one could make a good case for most of them.
The longevity-associated variant (LAV) of BPIFB4 was discovered using a stringent threshold of statistical significance for genome-wide association studies (GWAS) in three independent cohorts of centenarians in Italy, Europe, and the US. The LAV-BPIFB4 haplotype was inversely correlated with frailty in elderly subjects, strengthening its relevance in influencing the health status and longevity of the elderly.
Further analyses showed that the LAV homozygous genotype was positively associated with high endothelial nitric oxide (eNOS) phosphorylation in mononuclear cells, which translates to augmented nitric oxide (NO) production and beneficial functions in the cardiovascular system. In keeping with the benefits to the vascular compartment, recombinant LAV-BPIFB4 protein supplementation enhanced the proangiogenic activity of young and senescent endothelial cells. Importantly, these advantages can be transferred through LAV-BPIFB4 gene therapy in older mice, whereas eNOS phosphorylation and vessel activity are restored to levels observed in young mice.
Alongside the eNOS downstream substrate, the SDF-1/CXCR4 axis is a crucial effector of the cardiovascular protective and immunomodulatory activity of LAV-BPIFB4. In this regard, LAV-BPIFB4 activates SDF-1/CXCR4 signaling to remodel the immune system and resolve inflammation through various mechanisms involving protective macrophage polarization toward the pro-resolving M2 phenotype, favorable redistribution of circulating monocyte cell subsets, and reduction in T-cell activation.
View the full article at FightAging
