Vasohibin-1 Knockout Extends Life in Mice
Researchers here report on yet another genetic method to modestly slow aging in mice, to add to the numerous approaches already demonstrated. Like a range of other interventions that affect the pace of aging in mice, this appears to work at last partially through the well-studied insulin signaling pathway. That is usually a sign that the intervention in question is working through similar mechanisms to those triggered by the practice of calorie restriction, but may or may not be the case here given the specific details.
The vascular system is one of the major target organs affected by aging. In order to maintain vascular integrity, vascular endothelial cells (ECs) should have self-defense systems. We previously reported that vasohibin-1 (Vash1) could be one of such systems. Vash1 was originally isolated as an angiogenesis inhibitor was preferentially expressed in ECs for negative-feedback regulation. However, our subsequent analysis revealed that Vash1 has an additional function that causes an upsurge in stress resistance of ECs by increasing the expression of superoxide dismutase 2 (SOD2) and SIRT1 in ECs. Along with this finding, we observed that the decreased expression of Vash1 promotes vascular diseases such as diabetic nephropathy and atherosclerosis. We then noticed that the expression of Vash1 in ECs is downregulated with aging due to an increase in the expression of a certain microRNA, namely, miR-22. This observation raised the question as to why nature would allow a decrease in the expression of such a valuable protein with aging.
Because of the protective role of Vash1 in the vasculature, in this present study we assumed that vash1-/- mice would have a short lifespan. However, to our surprise, vash1-/- mice lived significantly longer and looked healthier than wild-type (WT) mice. We sought the cause of this healthy longevity and found that vash1-/- mice exhibited mild insulin resistance along with reduced expression of the insulin receptor (insr), insulin receptor substrate 1 (irs-1), and insulin receptor substrate 2 (irs-2) in their white adipose tissue (WAT) but not in their liver or skeletal muscle. The expression of vash1 dominated in the WAT among those 3 organs. Importantly, vash1-/- mice did not develop diabetes even when fed a high-fat diet. These results indicate that the expression of vash1 was required for the normal insulin sensitivity of the WAT and that the target molecules for this activity were insr, irs1, and irs2. The lack of vash1 caused mild insulin resistance without the outbreak of overt diabetes and might contribute to healthy longevity.