Genetic Mechanisms of Age Regulation of Blood Coagulation

Abstract

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, AE5Ј and AE3Ј, which are together essential for age regulation of the normal human factor IX (hFIX) gene. AE5Ј, present in the long interspersed repetitive element-derived sequence of the 5Ј 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. AE3Ј, present in the middle of the 3Ј untranslated region, is responsible for age-associated elevation of hFIX mRNA levels in the liver. Presence of both AE5Ј and AE3Ј 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. Key Words: aging Ⅲ homeostasis Ⅲ factor IX Ⅲ hemophilia Ⅲ cardiovascular disease Ⅲ thrombosis B lood coagulation plays a critical role not only in homeostasis but also in many physiological and pathological conditions. 1 Blood coagulation potential in humans as well as other mammals reaches a young adult level around the time of weaning, followed by a gradual increase during young adulthood and an almost 2-fold increase by old age. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] This advancing age-associated increase in coagulation potential takes place in healthy centenarians, 18 indicating that the increase is a normal age-associated phenomenon. However, it is conceivable that in the general human population, such increases in blood coagulation potential may substantially contribute to the development and progression of ageassociated cardiovascular and thrombotic disorders. 16,17,19 -21 This increase in blood coagulation potential is apparently due to the collective effects of increases in the plasma level of procoagulant factors, combined with only marginal increases or even decreases in the plasma levels of anticoagulation factors (such as antithrombin III and protein C) or of factors involved in fibrinolysis. 16,17,19 -21 The age-associated increase in blood coagulation potential represents a net increase in the coagulation activity and appears to be a strictly controlled phenomenon rather than a consequence of general agingassociated dysregulation of hemostasis....

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“…A similar phenomenon of increase in FIX levels has been observed in other organisms like humans and mice. [43][44][45] Knockdown of target genes was performed using the piggyback technique developed in our laboratory. It has been previously noted that injections of saline or nonspecific piggyback hybrids do not cause any significant difference in results.…”