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oai:repisalud.isciii.es:20.500.12105/72672024-11-29T15:01:07Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Derevyanko, Aksinya author Whittemore, Kurt author Schneider, Ralph P author Jiménez, Verónica author Bosch, Fàtima author Blasco , MA author 2017-12 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. Aging Cell. 2017;16(6):1353-1368. 10.1111/acel.12677 1474-9726 14749718 Aging cell 28944611 http://hdl.handle.net/20.500.12105/7267 Trf1 Adeno-associated serotype 9 vector Aging Shelterin Telomeres Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span