Gene therapy with the 1 telomere gene rescues decreased 1 levels with aging and prolongs mouse health span
Derevyanko, Aksinya (Centro Nacional de Investigaciones Oncológicas)
Whittemore, Kurt (Centro Nacional de Investigaciones Oncológicas)
Schneider, Ralph P. (Centro Nacional de Investigaciones Oncológicas)
Jiménez, Verónica (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Bosch i Tubert, Fàtima (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Blasco, María A. (Centro Nacional de Investigaciones Oncológicas)

Data:	2017
Resum:	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.
Ajuts:	Ministerio de Economía y Competitividad SAF2014-54886-R Ministerio de Economía y Competitividad SAF2013-45111-R
Nota:	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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Adeno-associated serotype 9 vector ; Aging ; Shelterin ; Telomeres ; Trf1
Publicat a:	Aging Cell, Vol. 16 (september 2017) , p. 1353-1368, ISSN 1474-9726

DOI: 10.1111/acel.12677
PMID: 28944611

16 p, 2.7 MB

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