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.
Highlights
Most people (80%) aged ≥80 years are frail and suffer from cardiovascular, metabolic, neurodegenerative disease, and cancer making aging the most important risk factor for late-onset diseases [1]
In aged mice we monitored an increase in SA-beta Gal activity in peripheral blood mononuclear cells (Fig. 1A)
60 days of AAV-LAV-BPIFB4 infection resulted in a significant decrease in senescent pool of peripheral immune cells and a concomitant enrichment of senescent cells in the spleen of AAV-LAV-BPIFB4 mice compared to old-GFP-mice
Summary
Most people (80%) aged ≥80 years are frail and suffer from cardiovascular, metabolic, neurodegenerative disease, and cancer making aging the most important risk factor for late-onset diseases [1]. An example is the age-related decline of the immune system (termed immunesenescence) that becomes less efficient in surveilling and protecting the organism from inflammatory conditions (inflammaging), contributing to the organism ageing [2]. Looking for causal factors in driving aging, the level of NAD+, the well-known nucleotide regulating cellular homeostasis [3], decreased during aging and in progeroid states, contributing to metabolic dysfunction and a decline in overall fitness [3–7]. Immune cells undergoing senescence, that is, expressing increased levels of p16INK4α, p21CIP1, and SA-beta Gal activity and showing a peculiar senescence-associated secretory phenotype (SASP), can drive the loss of tissue homeostasis, damage, and age-associated changes in several peripheral organs, contributing to reduced lifespan [8]. Cellular senescence trigger inflammaging and CD38+ inflammatory cells that lead to NAD+ decline
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