The Longevity Associated Variant of BPIFB4

In principle, genetic variants associated with longevity should help to point out which processes are more important in the aging process, and therefore steer researchers towards more effective approaches to interventions aimed at slowing or reversing aging. In practice, however, so few longevity-associated variants have been found that little has been accomplished on this front. One of them is examined in this open access paper. The mechanism by which it contributes to longevity may be a reduction in the burden of hypertension and consequent tissue damage.

To be clear, near any study of genetics and aging turns up all sorts of variants that correlate with longevity in the study population in question, but only a handful have ever been replicated in other study populations. This tells us that the genetics of aging is a matter of hundreds or thousands of tiny, interacting contributions, highly sensitive to environmental factors. This is why I am not optimistic that genetic studies of this nature are the road to any sort of meaningful progress towards greater human longevity. Even the variant here, if it operates via a lowering of blood pressure, is a poor substitute for long-standing drugs that achieve the same result to a greater degree, and those drugs were developed without any reference to the genetic study of longevity.

Frailty reflects the individual's biological age and life expectancy better than chronological age. Studies in long-living individuals (LLIs), which, in spite of their exceptional biological age, are protected from and cope better with age-related diseases, confirm this concept. Moreover, several genetic factors that are reportedly implicated in the determination of exceptional longevity are also inversely related with frailty disabilities.

The Bactericidal/Permeability-Increasing Fold-Containing Family B member 4 (BPIFB4) gene encodes a secreted protein, initially found to be expressed in salivary glands, and more recently discovered to play important pathophysiological roles at systemic level. A genome wide association study (GWAS), performed on an Italian set of LLIs and controls and validated on two independent populations from Germany and USA, identified the BPIFB4 variants associate with lifespan.

The BPIFB4 protein is expressed in undifferentiated and highly proliferative cells and in fetal/stressed heart tissue (cardiac hypertrophy), which share a common hypoxic environment. Overexpression of BPIFB4 isoforms induced the activation of stress response-related heat-shock proteins (HSPs) and the modification of protein homeostatic processes (translation, ribosome biogenesis, spliceosome), two processes that are usually lost during aging.

Furthermore, the circulating levels of immunoreactive BPIFB4 protein are reportedly higher in healthy LLIs than in diseased LLIs or young controls. Similarly, CD34+ hematopoietic cells and mononuclear cells (MNCs) of LLIs expressed higher levels of BPIFB4 than corresponding cells of young controls. Studies in experimental models of cardiovascular disease confirmed that overexpression of the human LAV-BPIFB4 gene results in attenuation of hypertension, atherosclerosis, and ischemic disease, which are hallmarks of aging.

Link: https://doi.org/10.18632/aging.102209

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