Genetic Mechanisms of Age Regulation of Blood Coagulation

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Abstract
—Blood coagulation capacity increases with age in healthy individuals, apparently because of increases in the plasma concentration of most procoagulant factors. This phenomenon may play an important role in the advancing age–associated increase of cardiovascular diseases and thrombosis. Through longitudinal analyses of transgenic mice, we recently identified 2 critical age-regulatory elements, AE5′ and AE3′, which are together essential for age regulation of the normal human factor IX (hFIX) gene. AE5′, present in the long interspersed repetitive element–derived sequence of the 5′ upstream region, containing polyomavirus enhancer activator-3 or a closely related element, is responsible for age-stable expression of the gene and functions in a position-independent manner. AE3′, present in the middle of the 3′ untranslated region, is responsible for age-associated elevation of hFIX mRNA levels in the liver. Presence of both AE5′ and AE3′ is needed to recapitulate normal age regulation of the hFIX gene. Because factor IX clearance from the circulation is not significantly affected by age, age regulation of hFIX levels is achieved primarily by a combination of stabilization of gene transcription and age-dependent increases in the mRNA levels, which are presumably due to increasing mRNA stabilization. The stage is now set for further systematic studies of the genetic and molecular mechanisms of age regulation of other key coagulation and anticoagulation factors in hopes of understanding the overall age regulation of blood coagulation.