Vascular calcification: an age-old problem of old age.

V ascular calcification, once considered a passive consequence of aging, is now recognized to be a highly regulated process akin to bone formation. Vascular calcification is prevalent across ethnicities and age groups, and observational studies show an interaction with aging in asymptomatic adults and in individuals with established coronary artery disease. Recent findings from the HORUS study have shown that the link between aging and vascular calcification is an age-old association. In this study, 137 mummies up to 4000 years old were examined with computed tomography scans. Vascular calcification was present in 47 of 137 or 34% of the mummies, and age at the time of death correlated positively with the presence of vascular calcification and the number of vascular beds with calcified vessels. 3 In the modern era, the incidence of vascular calcification has been shown to increase with advancing age and has been reported to be <5% annually for individuals <50 years of age to >12% for individuals >80 years of age. 2 When present, vascular calcification portends a worse clinical outcome; a meta-analysis of 218 000 patients found a 3.94-fold higher risk for cardiovascular mortality and a 3.41-fold higher risk for any cardiovascular event. 4 Thus, understanding how aging influences the pathobiology of vas-cular calcification may have far-reaching implications for associated cardiovascular morbidity and mortality. To understand the cellular and molecular mechanisms that underlie aging-related vascular calcification, investigators have begun to focus on the vascular pathophenotype associated with Hutchinson-Gilford progeria syndrome (HGPS). This rare genetic disorder is the result of a point mutation in the LMNA gene that generates an abnormal variant of prelamin A that retains its farnesyl group and is known as progerin. 5 The disease is characterized in part by accelerated aging with early atherosclerosis and vascular calcification. To date, the causative mechanisms for precocious vascular calcification in this disease have not been elucidated fully. In this issue of Circulation, Villa-Bellosta et al 6 report that vascular calcification in HGPS results from decreased levels of extracellular inorganic pyrophosphate, an inhibitor of hydroxyapatite crystal formation and ectopic calcification. Using the Lmma G609G knock-in mouse model of HGPS, which expresses progerin and has pronounced aortic medial calcifi-cation, the investigators found that low levels of extracellu-lar inorganic pyrophosphate occurred as a result of impaired synthesis and increased hydrolysis to inorganic phosphate. Pyrophosphate synthesis was impaired by substrate availability ; HGPS vascular smooth muscle cells (VSMCs) generated lower …