Scientists at the Gladstone Institutes in San Francisco have discovered a key mechanism that protects mice from developing a human disease of aging, and begins to explain the wide spectrum of disease severity often seen in humans. Both aspects center on the critical role of telomeres, protective caps on the ends of chromosomes that erode with age. Erosion of telomeres has long been associated with diseases of aging, but how telomere length affects human disease has remained largely a mystery. Now, scientists find that shortening telomeres in mice carrying a human genetic mutation linked to heart disease results in a deadly buildup of calcium in heart valves and vessels. This innovative model allows the researchers to test viable new drugs for this disease, and it provides a potential solution to studying other human disorders of aging in mice. Calcific aortic valve disease (CAVD) causes calcium to accumulate in heart valves and vessels until they harden like bone. It can only be treated by replacing the valve through heart surgery and is the third leading cause of heart disease, affecting 3 percent of adults over the age of 75. CAVD develops with age, and it can be caused by a mutation in one of two copies of the NOTCH1 gene. Humans typically have two copies of each gene. When one copy is lost, the remaining gene may not produce enough of its protein to sustain normal function. While reducing protein levels by half often causes disease in humans, mice with the same change are frequently protected from disease, but scientists have been unsure why. In the new study, published online on March 27, 2017 in the Journal of Clinical Investigation, the Gladstone scientists linked telomere length to risk for, or resistance to, these types of diseases.
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