Gene Therapy Delivering the Longevity-Associated Variant of BPIFB4 Improves Immune Function in Old Mice
In recent years, researchers have identified a variant of the gene BPIFB4 that correlates with longevity in humans, and in mice appears to suppress mechanisms in immune cells that contribute to chronic inflammation. In this paper, researchers use gene therapy to deliver the longevity-associated variant of BPIFB4 to old mice, and find that it reduces the presence of inflammatory immune cells showing markers of cellular senescence. The chronic inflammation of aging is known to contribute to many different age-related conditions, and the growing presence of senescent cells provides a sizable fraction of that inflammatory signaling. It is an important goal to find ways to suppress it without interfering in the necessary short-term inflammation needed to respond to infection and injury.
As we age, our body experiences chronic, systemic inflammation contributing to the morbidity and mortality of the elderly. The senescent immune system has been described to have a causal role in driving systemic aging and therefore may represent a key therapeutic target to prevent pathological consequences associated with aging and extend a healthy lifespan. Previous studies from our group associated a polymorphic haplotype variant in the BPIFB4 gene (LAV-BPIFB4) with exceptional longevity. Transfer of the LAV-BPIFB4 in preclinical models halted the progression of cardiovascular diseases (CVDs) and frailty by counterbalancing chronic inflammation.
In the present study, we aimed to delineate the action of systemic adeno-associated viral vector-mediated LAV-BPIFB4 gene transfer (AAV-LAV-BPIFB4) on the deleterious age-related changes of the immune system and thereby the senescence-associated events occurring in C57BL/6J mice aged 26 months. Our in vivo data showed that 26-months-old mice had a higher frequency of CD45+SA-beta Gal+ immune cells in peripheral blood than young (4-months-old) C57BL/6J mice. Notably, AAV-LAV-BPIFB4 gene transfer in aged mice reduced the pool of peripheral immunosenescent cells that were shown to be enriched in the spleen. In addition, the proper tuning of the immune secretory phenotype (IL1βlow, IL6low, IL10high) associated with a significant reduction in SA-beta Gal-positive area of aorta from AAV-LAV treated mice.
At the functional level, the reduction of senescence-associated inflammation ensured sustained NAD+ levels in the plasma of AAV-LAV-BPIFB4 old mice by preventing CD38 increase in F4/80+ tissue-resident macrophages and Ly6Chigh pro-inflammatory monocytes of the spleen and bone marrow. Finally, to validate the clinical implication of our findings, we showed that Long-living-individuals (LLIs, older than 95 years), which delay CVDs onset, especially if LAV-carriers, were characterized by high NAD+ levels. In conclusion, the new senotherapeutic action of LAV-BPIFB4 may offer a valuable therapeutic tool to control aging and reduce the burden of its pathophysiological disorders, such as CVDs.
For how long? If we've learned anything in the last 2 years, it is that improved immune function delivered with gene therapy may decline and even reverse over time. I think a look at the effects on NHEJ function should be standard protocol for any gene therapy from now on.