Genetic mechanisms of age regulation of blood coagulation factor IX model

Blood coagulation capacity increases with age in healthy individuals, appar ently because of increases in the plasma concentration of most procoagulant factors. This phenomenon may play an important role in the advancing age-a ssociated increase of cardiovascular diseases and thrombosis. Through longi tudinal analyses of transgenic mice, we recently identified 2 critical age- regulatory elements, AE5' and AE3', which are together essential for age re gulation of the normal human factor IX (hFIX) gene. AE5', present in the lo ng interspersed repetitive element-derived sequence of the 5' upstream regi on, containing polyomavirus enhancer activator-3 or a closely related eleme nt, is responsible for age-stable expression of the gene and functions in a position-independent manner. AE3', present in the middle of the 3' untrans lated region, is responsible for age-associated elevation of hFIX mRNA leve ls in the liver. presence of both AE5' and AE3' is needed to recapitulate n ormal age regulation of the hFIX gene. Because factor IX clearance from the circulation is not significantly affected by age, age regulation of hFIX l evels is achieved primarily by a combination of stabilization of gene trans cription and age-dependent increases in the mRNA levels, which are presumab ly due to increasing mRNA stabilization. The stage is now set for further s ystematic studies of the genetic and molecular mechanisms of age regulation of other key coagulation and anticoagulation factors in hopes of understan ding the overall age regulation of blood coagulation.