Klotho is one of the few robustly determined longevity genes capable of altering life span in both directions in mice. A reduced expression of klotho shortens life span, while increased klotho levels lengthen life. Klotho has been shown to improve cognitive function, but investigation to date has suggested that it primarily functions in the kidney, and that kidney function mediates effects elsewhere in the body.
Today's open access paper is focused instead on the relationship between klotho and vascular calcification. Prior research on this topic has focused on the relationship between klotho and FGF23, but here the authors are interested in how klotho affects the cellular maintenance processes of autophagy. Efficiency and amount of autophagy may determine FGF23 expression; as is always the case, biochemistry is a web of connections.
Autophagy has a complex relationship with calcification, and calcification itself is a complex phenomenon. In essence cells in the vasculature change to adopt characteristics of osteoblasts, responsible for generating bone tissue. This is the result of changes in the signaling environment, with many contributing causes, including chronic inflammation. Greater autophagy can in principle slow calcification by amending cell behavior to reduce bone-formation activities, and correlations between greater autophagy and lesser calcification are observed. Yet there are mechanisms by which autophagy and its outcomes might accelerate processes of calcification.
Vascular calcification (VC) is associated with increased risk of major adverse cardiovascular events in several clinical conditions, such as chronic kidney disease and atherosclerosis and aging. The formation of VC is associated with complex pathological mechanisms, including osteogenic differentiation and apoptosis of vascular smooth muscle cells (VSMCs) and release of matrix vesicles loaded calcium (Ca) and phosphate (Pi). By inhibiting these processes, VC can be effectively treated.
Klotho, a protein highly expressed in the kidney, is thought to be involved in various aging-associated pathologies. Studies have reported that Klotho-deficient mice developed obvious aortic VC, which can be reversed by Klotho overexpression. To date, the mechanisms whereby Klotho protects against VC have focused on not only its role as an obligate co-factor for FGF23 signaling in regulating Pi and vitamin D systems in kidney, but also its direct effects on the vasculature as a circulating anti-calcific factor. However, the mechanisms of this direct effects have not yet been fully explored.
Growing evidence indicates that autophagy, defined as the dynamic, refined, and controlled process of cellular self-digestion, protects VSMCs against calcification. Although autophagic activity reportedly increases in the aorta of Klotho-deficient mice, its role in the Klotho's regulation of VC remains unclear. The present study investigated whether Klotho deficiency could induce protectively-increased autophagy and whether Klotho administration ameliorated calcification through said autophagy increase.
Results indicated that, based on Agatston score, serum Klotho level was negatively associated with aortic calcification. Then, Klotho-deficient mice exhibited aortic VC, which could be alleviated with the supplementation of Klotho protein. Moreover, autophagy increased in the aorta of Klotho-deficient mice and protected against VC. Finally, we found that Klotho ameliorated calcification by promoting autophagy both in the aorta of Klotho-deficient mice and in mouse vascular smooth muscle cells under calcifying conditions. These findings indicate that Klotho deficiency induces increased autophagy to protect against VC and that Klotho expression further enhances autophagy to ameliorate calcification.