Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span

The shelterin complex protects telomeres by preventing them from being degraded and recognized as double-strand DNA breaks. TRF1 is an essential component of shelterin, with important roles in telomere protection and telomere replication. We previously showed that TRF1 deficiency in the context of d...

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Authors: Derevyanko, Aksinya, Whittemore, Kurt, Schneider, Ralph P, Jiménez, Verónica, Bosch, Fàtima, Blasco , MA
Format: article
Publication Date:2017
Country:España
Institution:Instituto de Salud Carlos III (ISCIII)
Repository:Repisalud
Language:English
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/7267
Online Access:http://hdl.handle.net/20.500.12105/7267
Access Level:Open access
Keyword:Aging
Animals
Cloning, Molecular
DNA Damage
Dependovirus
Genetic Therapy
Genetic Vectors
HEK293 Cells
Humans
Mice
Mice, Inbred C57BL
Telomere
Telomeric Repeat Binding Protein 1
Transfection
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oai_identifier_str oai:repisalud.isciii.es:20.500.12105/7267
network_acronym_str ES
network_name_str España
repository_id_str
spelling Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health spanDerevyanko, AksinyaWhittemore, KurtSchneider, Ralph PJiménez, VerónicaBosch, FàtimaBlasco , MAAgingAnimalsCloning, MolecularDNA DamageDependovirusGenetic TherapyGenetic VectorsHEK293 CellsHumansMiceMice, Inbred C57BLTelomereTelomeric Repeat Binding Protein 1TransfectionThe shelterin complex protects telomeres by preventing them from being degraded and recognized as double-strand DNA breaks. TRF1 is an essential component of shelterin, with important roles in telomere protection and telomere replication. We previously showed that TRF1 deficiency in the context of different mouse tissues leads to loss of tissue homeostasis owing to impaired stem cell function. Here, we show that TRF1 levels decrease during organismal aging both in mice and in humans. We further show that increasing TRF1 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 (AAV9), which transduces the majority of mouse tissues allowing for moderate and transient TRF1 overexpression. AAV9-TRF1 gene therapy significantly prevented age-related decline in neuromuscular function, glucose tolerance, cognitive function, maintenance of subcutaneous fat, and chronic anemia. Interestingly, although AAV9-TRF1 treatment did not significantly affect median telomere length, we found a lower abundance of short telomeres and of telomere-associated DNA damage in some tissues. Together, these findings suggest that rescuing naturally decreased TRF1 levels during mouse aging using AAV9-TRF1 gene therapy results in an improved mouse health span.WileyBotín FoundationMinisterio de Economía y Competitividad (España)20192019-03-0120172017-12-0120172017-12-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfapplication/vnd.ms-powerpointhttp://hdl.handle.net/20.500.12105/7267reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengES SAF2014-54886-R Not availableES SAF2013-45111-R Not availableopen accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/72672026-06-12T12:43:37Z
dc.title.none.fl_str_mv Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span
title Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span
spellingShingle Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span
Derevyanko, Aksinya
Aging
Animals
Cloning, Molecular
DNA Damage
Dependovirus
Genetic Therapy
Genetic Vectors
HEK293 Cells
Humans
Mice
Mice, Inbred C57BL
Telomere
Telomeric Repeat Binding Protein 1
Transfection
title_short Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span
title_full Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span
title_fullStr Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span
title_full_unstemmed Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span
title_sort Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span
dc.creator.none.fl_str_mv Derevyanko, Aksinya
Whittemore, Kurt
Schneider, Ralph P
Jiménez, Verónica
Bosch, Fàtima
Blasco , MA
author Derevyanko, Aksinya
author_facet Derevyanko, Aksinya
Whittemore, Kurt
Schneider, Ralph P
Jiménez, Verónica
Bosch, Fàtima
Blasco , MA
author_role author
author2 Whittemore, Kurt
Schneider, Ralph P
Jiménez, Verónica
Bosch, Fàtima
Blasco , MA
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Botín Foundation
Ministerio de Economía y Competitividad (España)
dc.subject.none.fl_str_mv Aging
Animals
Cloning, Molecular
DNA Damage
Dependovirus
Genetic Therapy
Genetic Vectors
HEK293 Cells
Humans
Mice
Mice, Inbred C57BL
Telomere
Telomeric Repeat Binding Protein 1
Transfection
topic Aging
Animals
Cloning, Molecular
DNA Damage
Dependovirus
Genetic Therapy
Genetic Vectors
HEK293 Cells
Humans
Mice
Mice, Inbred C57BL
Telomere
Telomeric Repeat Binding Protein 1
Transfection
description The shelterin complex protects telomeres by preventing them from being degraded and recognized as double-strand DNA breaks. TRF1 is an essential component of shelterin, with important roles in telomere protection and telomere replication. We previously showed that TRF1 deficiency in the context of different mouse tissues leads to loss of tissue homeostasis owing to impaired stem cell function. Here, we show that TRF1 levels decrease during organismal aging both in mice and in humans. We further show that increasing TRF1 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 (AAV9), which transduces the majority of mouse tissues allowing for moderate and transient TRF1 overexpression. AAV9-TRF1 gene therapy significantly prevented age-related decline in neuromuscular function, glucose tolerance, cognitive function, maintenance of subcutaneous fat, and chronic anemia. Interestingly, although AAV9-TRF1 treatment did not significantly affect median telomere length, we found a lower abundance of short telomeres and of telomere-associated DNA damage in some tissues. Together, these findings suggest that rescuing naturally decreased TRF1 levels during mouse aging using AAV9-TRF1 gene therapy results in an improved mouse health span.
publishDate 2017
dc.date.none.fl_str_mv 2017
2017-12-01
2017
2017-12-01
2019
2019-03-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/7267
url http://hdl.handle.net/20.500.12105/7267
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv ES SAF2014-54886-R Not available
ES SAF2013-45111-R Not available
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/vnd.ms-powerpoint
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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