title: The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence.
abstract: Here, we show that a small-molecule activator of telomerase (TA-65) purified from the root of Astragalus membranaceus is capable of increasing average telomere length and decreasing the percentage of critically short telomeres and of DNA damage in haploinsufficient mouse embryonic fibroblasts (MEFs) that harbor critically short telomeres and a single copy of the telomerase RNA Terc gene (G3 Terc(+/-) MEFs). Importantly, TA-65 does not cause telomere elongation or rescue DNA damage in similarly treated telomerase-deficient G3 Terc(-/-) littermate MEFs. These results indicate that TA-65 treatment results in telomerase-dependent elongation of short telomeres and rescue of associated DNA damage, thus demonstrating that TA-65 mechanism of action is through the telomerase pathway. In addition, we demonstrate that TA-65 is capable of increasing mouse telomerase reverse transcriptase levels in some mouse tissues and elongating critically short telomeres when supplemented as part of a standard diet in mice. Finally, TA-65 dietary supplementation in female mice leads to an improvement of certain health-span indicators including glucose tolerance, osteoporosis and skin fitness, without significantly increasing global cancer incidence.
authors.affiliation: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre, Melchor Fernández Almagro 3, Madrid, Spain.
authors.forename: Bruno
authors.initials: B
authors.lastname: Bernardes de Jesus
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schneeberger
authors.forename: Elsa
authors.initials: E
authors.lastname: Vera
authors.forename: Agueda
authors.initials: A
authors.lastname: Tejera
authors.forename: Calvin B
authors.initials: CB
authors.lastname: Harley
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D027885:Astragalus propinquus / Q000737:chemistry; D004249:DNA Damage; D004032:Diet; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D016588:Anticarcinogenic Agents; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase