Transfer of the longevity-associated variant of BPIFB4 gene rejuvenates immune system and vasculature by a reduction of CD38+ macrophages and NAD+ decline

Abstract

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 the NADase 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, >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.

Accelerated Cardiac Aging in Patients With Congenital Heart Disease

“…The related mutant protein forms a complex with 14-3-3 and HSP90, activating the prosurvival eNOS—Akt signaling. Supplementation of the longevity genes significantly improved cardiac function in different models of age-related cardiac disease ( 188 – 191 ) and reverse immune senescence ( 192 ). It would be interesting to determine the expression of BPIFB4 in CHD and, if this is found downregulated as in elderly cardiovascular patients ( 193 ), to assess the benefit of supplementation on cardiac cells from CHD patients and CHD models.…”

Gender Differences Associated with the Prognostic Value of BPIFB4 in COVID-19 Patients: A Single-Center Preliminary Study

“…We have already reported that higher BPIFB4 levels play a protective role in many disease conditions which are particularly associated with frailty in old males, such as diabetes [ 41 ], atherosclerosis [ 26 ], endothelial dysfunction and heart failure [submitted], in which gene therapy approaches leading to an improvement of its function may represent a potential therapeutic pathway. In addition, a variant of BPIFB4 gene that has been found to be associated with higher protein levels can selectively counteract some features of immunesenescence in vitro and in vivo [ 27 ]. Immunesenescence, the phenotypic and functional impairment of the immune responses occurring as we age, is a predisposing risk factor for the development of COVID-19 [ 42 ].…”

“…More recently the transfer of the longevity-associated variant of BPIFB4 gene, which determines its rapid enrichment both in blood and target tissues, has been described to rejuvenate the immune system and vasculature. From a functional point of view, the reduction of senescence-associated inflammation (SASP) ensured sustained NAD+ levels in the plasma of treated mice by preventing the NADase CD38 increase in F4/80+ tissue-resident macrophages [ 27 ]. This is an interesting action as the level of NAD+, a well-known nucleotide regulating cellular homeostasis that is lost as we age, contributes to metabolic dysfunction and a decline in overall fitness [ 28 ].…”

Effects of Human LAV-BPIFB4 Gene Therapy on the Epigenetic Clock and Health of Aged Mice

“…The BPIFB4 protein, implicated in activating homeostatic processes such as adaptive stress response and proteostasis, is found at high levels in the serum of long-living people and the LAV-BPIFB4 genetic variant has been associated with healthy aging and exceptional longevity [ 19 ]. In addition, the LAV-BPIFB4 gene therapy in mouse models has been proven to rescue the age-related endothelial dysfunction [ 20 ], reduce the progression of cardiovascular diseases [ 21 ], delay heart aging [ 22 ], and decrease the pool of senescent cells and senescence-associated inflammation [ 23 , 24 ]. In such pre-clinical studies, the LAV-BPIFB4 gene was delivered through an adeno-associated virus (AAV serotype 9) carrying a liver-specific promoter.…”