Conclusion
Aging-associated arterial stiffening may be largely attributed to downregulation of B-cell population and serum IgG levels. AAV-SKL attenuates arterial stiffness in aging mice partly via restoring B-cell population and serum IgG levels which attenuates aging-associated vascular inflammation and arterial remodeling.
Objective
Aging is associated with compromised immune function and arterial remodeling and stiffness. The purpose of this study is to investigate whether in vivo AAV-based delivery of secreted Klotho (SKL) gene (AAV-SKL) improves aging- and senescence-associated immune dysfunction and arterial stiffness.
Results
Senescence-accelerated mice prone strain 1 (SAMP1, 10 months) and old mice (20 months) were used. Serum SKL levels, B-cell population and serum IgG levels were markedly decreased in SAMP1 and old mice. Rescue of downregulation of serum SKL levels by in vivo AAV2-based delivery of SKL gene (AAV-SKL) increased B-cell population and serum IgG levels and attenuated arterial stiffness in SAMP1 and old mice. Thus, Klotho deficiency may play a role in senescence- and aging-associated humoral immune dysfunction and arterial stiffness. Vascular infiltration of inflammatory cells and expression of TGFβ1, collagen 1, scleraxis, MMP-2 and MMP-9 were increased while the elastin level was decreased in aortas of SAMP1 and old mice which can be rescued by AAV-SKL. Interestingly, treatment with IgG effectively rescued arterial inflammation and remodeling and attenuated arterial stiffness and hypertension in aging mice. In cultured B-lymphoblast cells, we further showed that SKL regulates B-cell proliferation and maturation partly via the NFkB pathway.