AK050834 Deficiency Prevents Vascular Aging via Opposite Regulation of Two Senescence-Sensitive Genes ATF3 and p21.

Vascular aging, not only a victim of vascular cell senescence but also a driving hub of systemic aging, is a complex process in which both anti-aging and pro-aging proteins are involved. Thus, the ideal anti-aging medication should have multiple protein targets; in this case, an lncRNA might be a good choice. AK050834 is a conserved lncRNA, but its roles in vascular biology and vascular aging are currently unknown. Here, we identified that AK050834 was highly expressed in vascular walls and in vascular smooth muscle cells (VSMCs). Notably, AK050834 expression was remarkably increased in aged vessels. By using gain-of-function, loss-of-function, and gene knockout approaches, we identified that AK050834 is a strong regulator of VSMC senescence and vascular aging. In terms of the mechanisms, we found that AK050834 suppressed the expression of the anti-aging protein ATF3 via direct interaction with its promoter, which was further confirmed by a rescue experiment. In addition, AK050834 increased the expression of the pro-aging protein p21 by stabilizing its mRNA. Finally, we found that AK050834 deficiency could effectively prevent vascular aging in mice in vivo. The interesting dual and opposite effects of AK050834 on the anti-aging protein ATF3 and the pro-aging protein p21 suggest that AK050834 might be a novel diagnostic marker as well as an ideal therapeutic and preventive target for vascular aging and many related diseases.