Longer telomeres protect against valve calcification in mice
Calcific aortic valve disease (CAVD) is the 3rd largest cause of heart disease, and involves a progressive build-buildup of calcium in cardiac vessels and valves, which has disastrous consequences. CAVD is caused by mutations in the Notch1 gene and also rises in prevalence with age - affecting 3% of adults over 75.
"Our findings reveal a critical role for telomere length in a mouse model of age-dependent human disease. This model provides a unique opportunity to dissect the mechanisms by which telomeres affect age-dependent disease and also a system to test novel therapeutics for aortic valve disease"
Unravelling the role of telomeres in CAVD
Surprisingly, mice with one mutations in Notch1 are protected from the disease, and after some delving researchers from the Gladstone Institute and Stanford found that longer telomeres were likely behind the protection. Laboratory mice display longer telomeres in contrast to humans. When researchers deliberately engineered mice with both a Notch1 mutation and shortened telomeres, they found they displayed striking calcification in a manner similar to the human form of the disease. This suggests that while Notch1 mutations can lead to the condition, shortened telomeres may play a critical role in older individuals too.
Indeed, prior research has suggested that some patients with valve calcification have shorter telomeres in comparison to healthy individuals of the same age. The researchers theorised that telomere length was affecting gene expression and diminishing the expression of anti-inflammatory and anti-calcification pathways.
"Historically, we have had trouble modeling human diseases caused by mutation of just one copy of a gene in mice, which impedes research on complex conditions and limits our discovery of therapeutics. Progressive shortening of longer telomeres that are protective in mice not only reproduced the clinical disease caused by NOTCH1 mutation, it also recapitulated the spectrum of disease severity we see in humans"
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