By David N. Leff
Age spots and age clots have two things in common. For one thing, they rhyme. For another, they both reflect physical hallmarks that arise with advancing years.
Age spots ¿ hyperpigmented cafi-au-lait blotches on the epidermis ¿ are well known, thanks to advertising by over-the-counter skin-bleaching creams. Age clots ¿ blood-coagulation potential that increases with the passing birthdays ¿ is less familiar, because this gradual blood-thickening is perfectly natural, and usually imperceptible.
¿The phenomenon of blood-coagulation increase as we get old,¿ observed molecular geneticist and biochemist Kotoku Kurachi, ¿is a very normal phenomenon. Even centenarians who live to be over 100 years old in good health show this typical increase. Some people who live to be over 100,¿ he pointed out, ¿have a genetic or dietary or environmental element that enables them to live normal and healthy lives. Those people must have some mechanism that inhibits atherosclerosis from developing, and therefore the frequency of cardiovascular disease [CVD] is so low in that age group.
¿Unfortunately,¿ he continued, ¿we call ourselves a normal population, and most people in it will be fine, but still develop CVD, thrombosis or stroke as they get old. They have that risk, that propensity, and then increased blood-coagulation activity will contribute tremendously ¿ we are almost certain ¿ to those diseases.¿
Kurachi, a professor of human genetics at the University of Michigan in Ann Arbor, has spent the past decade trying to get to the molecular bottom of what causes this blood-thickening phenomenon of aging. His latest research finding appears in today¿s issue of Science, dated July 30, 1999, and titled: ¿Genetic mechanisms of age regulation of human blood coagulation factor IX.¿
FIX Protein Pivots Delicate Bleeding Balance
¿We started working on factor IX [FIX],¿ Kurachi told BioWorld Today, ¿because it is one of the key blood-coagulation proteins. Everybody has about 5 micrograms per milliliter of FIX in his or her blood. And of course, that gradually goes up as we get old. If the coagulation activity increases, then it tips the balance between forming a clot and dissolving a clot. If the balance is tipped to the blood-coagulation side, then we have a higher risk of thrombotic disease, stroke and CVD. If it tips to the other side, then we have abnormal bleeding, which ¿ in one who lacks FIX ¿ typically ends up as hemophilia.¿
Kurachi made the point, ¿More than two dozen protein factors are involved in the blood-coagulation cascade. We couldn¿t look at the whole thing. We had to start somewhere, particularly for finding out the molecular and genetic mechanism. So that¿s why we focused on FIX to begin with, and started long-term studies.¿
By ¿long-term,¿ the Michigan scientist meant nothing less than raising several generations of transgenic mice, expressing various segments of the FIX gene, and monitoring their changing blood-coagulation levels from birth to death of old age, at about 24 months. They also monitored, from birth to death, two to four generations of mice descended from each founder animal. Here is how Kurachi and his co-authors went about it:
¿The natural human FIX gene,¿ he noted, ¿is very large, about 40 kilobases on the X chromosome, so it¿s very difficult to handle. Therefore, after trials and errors, we constructed minigenes, between 3 kb and 5 kb long. These are composed of various key portions of the native human FIX gene, including a gene expression control sequence, of course a protein coding region, and also neighboring parts of the full-length gene.¿
He and his team have made more than 20 separate combinations of these components, of which they tested more than 11, as reported in Science. ¿For each minigene construct,¿ Kurachi recounted, ¿we generated transgenic mice. To study their aging factor, we had to longitudinally analyze hundreds of the animals individually, not as a group. So every month throughout their entire life span, we drew a blood sample from each mouse and measured the FIX level in its circulation.
¿By studying each construct one by one,¿ he went on, ¿we realized that one part of the gene, which we named age element 5-prime [AE54] has a very critical role in the stable expression of FIX. But that didn¿t give us this increase in FIX expression with advancing age. Then we further found that an AE34 portion of the gene is also needed. So together, these two elements let us recapitulate what the natural FIX gene is doing.¿
Why Blood Is Thicker In Elderly
¿I think the significance of this finding is great,¿ Kurachi said, ¿because we believe it to be the first time the molecular mechanism of what¿s going on in the regulation of the blood-coagulation factor has been shown. We call it typically a mechanism of homeostasis. It explains why coagulation capacity is almost twice as high in older people and other mammals as it is in young adults.
¿When mammals are born,¿ he explained, ¿the coagulation capacity of their blood is only 40 to 45 percent that of a young adult¿s. By weaning age, it reaches young-adult levels, and continues to increase gradually during adulthood. Blood coagulation is one of the body¿s fundamental defense systems. We have to have the blood clot; otherwise, when we cut a finger we lose blood.¿
Kurachi added, ¿We believe that the information we have obtained through this study provides new targets for developing pharmaceutical drugs to control CVD or thrombosis or stroke ¿ particularly for old people. Once we completely understand this very complex system,¿ he concluded, ¿we should be able to design new pharmaceutical compounds to modulate increases in coagulation activity as we age.¿ The university has applied for patents covering the gene elements found in Kurachi¿s study.