Piperlongumine, an extract of long peppers, was shown to be senolytic a few years ago. The compound is capable of selectively destroying senescent cells by sensitizing them to oxidative damage, provoking apoptosis. The accumulation of senescent cells is one of the causes of aging, and means of clearance are thus potentially valuable. For those considering introducing more long peppers into their diet, note that a senolytic dose of piperlongumine would require ingesting an impossibly large weight of pepper. Just a few peppers will do absolutely nothing, as they contain far too little piperlongumine individually to make any difference.
Interestingly, this discovery doesn't appear to have made its way all that far into that part of the research community that works with piperlongumine on a regular basis. I keep seeing papers in which scientists report on the evaluation of piperlongumine as a treatment for an age-related condition that is known to be caused in part by cellular senescence, in which there is no mention of senescent cells. It is odd.
Today's open access paper is an example of the type, in which piperlongumine is deployed to treat aortic calcification, a cause of vascular stiffness, hypertension, and consequent cardiovascular disease. There is good evidence for senescent cells to contribute to this process via their secretions, inflammatory signaling that causes cells in blood vessel walls to begin to behave as though they are in bone tissue, depositing calcium into the extracellular matrix. Not that you would learn that from this paper, which focuses instead on the downstream changes that take place in these misbehaving blood vessel cells.
Vascular calcification is a complex disease that can occur in large and small blood vessels throughout the body. The main feature of vascular calcification is the deposition of calcium-containing complexes along the blood vessel wall. These deposits are mainly composed of calcium and phosphate minerals in the form of hydroxyapatite crystals, which are similar to those in bone tissue. Vascular calcification is now recognized as an active biological process that shares many features with physiological bone formation. There are many causes of vascular calcification, including diabetic angiopathy, chronic kidney disease, lipid metabolism disorders, and genetic factors. Currently, no theory completely explains the pathogenesis of vascular calcification, and no specific treatment methods for vascular calcification are preferred. Therefore, the search for effective treatment methods for vascular calcification is of great significance for the future protection of human cardiovascular health.
Vascular smooth muscle cells (VSMCs) are thought to constitute the main cell type in vascular calcification. In calcified blood vessels, VSMCs show osteogenic differentiation, that is, transformation from a contractile phenotype to a bone/cartilage mineralized phenotype, which is characterized by the development of calcified vesicles, downregulation of mineralization-inhibiting molecules, and increased calcified matrix. This transformation is accompanied by loss of the smooth muscle cell marker smooth muscle 22 alpha (SM22α) and increase in osteochondrocyte markers, including runt-related transcription factor 2 (Runx2), bone morphogenetic protein 2 (Bmp2), osteopontin (OPN), osteocalcin, and alkaline phosphatase (ALP). Overexpression of Bmp2 in vascular smooth muscle cells increases the level of calcification, and Bmp2 expression is increased in the calcified atherosclerotic plaques of blood vessels.
Piperlongumine is a cell-permeable, orally bioavailable natural product isolated from the Piper longum L. plant species. The reported pharmacological activities of PLG include anti-inflammatory, antibacterial, anti-atherosclerotic, antioxidant, antitumour, antiangiogenic and anti-diabetic activities. In this study, we determined the effect of PLG on high calcium- and phosphate-induced vascular calcification, and we further explored its potential molecular mechanisms.
In vitro, PLG inhibited calcium deposition of VSMCs treated with high calcium/phosphate medium. PLG also decreased the expression of osteogenic genes and proteins, including Runx2, Bmp2, and OPN. In a vitamin D-induced aortic calcification mouse model, a 5 mg/kg dose of PLG decreased calcium deposition in the aortic wall as well as Runx2 expression. With regard to the mechanism, we found that the levels of P53 mRNA and protein in both VSMCs and mouse aortic tissues were decreased in the calcification models, and we observed that PLG preserved the levels of P53 and its downstream gene PTEN. Concurrent treatment of VSMCs with P53 ShRNA and PLG blunted the anti-calcific effect of PLG. In conclusion, PLG attenuates high calcium/phosphate-induced vascular calcification by upregulating P53/PTEN signaling in VSMCs.