Gene therapy with the 1 telomere gene rescues decreased 1 levels with aging and prolongs mouse health span

Abstract

Altres ajuts: Research in Maria Blasco's laboratory is funded by the Ministerio de Economía y Competitividad, Plan Nacional I+D+I (SAF2013-45111-R), and by the Fundación Botín.The shelterin complex protects telomeres by preventing them from being degraded and recognized as double-strand breaks. 1 is an essential component of shelterin, with important roles in telomere protection and telomere replication. We previously showed that 1 deficiency in the context of different mouse tissues leads to loss of tissue homeostasis owing to impaired stem cell function. Here, we show that 1 levels decrease during organismal aging both in mice and in humans. We further show that increasing 1 expression in both adult (1-year-old) and old (2-year-old) mice using gene therapy can delay age-associated pathologies. To this end, we used the nonintegrative adeno-associated serotype 9 vector (9), which transduces the majority of mouse tissues allowing for moderate and transient 1 overexpression. 9-1 gene therapy significantly prevented age-related decline in neuromuscular function, glucose tolerance, cognitive function, maintenance of subcutaneous fat, and chronic anemia. Interestingly, although 9-1 treatment did not significantly affect median telomere length, we found a lower abundance of short telomeres and of telomere-associated damage in some tissues. Together, these findings suggest that rescuing naturally decreased 1 levels during mouse aging using 9-1 gene therapy results in an improved mouse health span