The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence

Aging Cell

Volumn 10, Issue 4, 2011, Pages 604-621

  de Jesus, Bruno Bernardes ^a   Schneeberger, Kerstin ^a   Vera, Elsa ^a,b   Tejera, Agueda ^a   Harley, Calvin B ^c   Blasco, Maria A ^a  

^a Centro Nacional de Investigaciones Oncológicas   (Spain)

^b Life Length   (Spain)

^c Telome Health   (United States)

Author keywords

Aging; Mouse; TA 65; Telomerase activation; Telomere length

Indexed keywords

ASTRAGALUS MEMBRANACEUS EXTRACT; RNA; TA 65; TELOMERASE; TELOMERASE REVERSE TRANSCRIPTASE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; ASTRAGALUS MEMBRANACEUS; CANCER INCIDENCE; CONTROLLED STUDY; DIET SUPPLEMENTATION; DNA DAMAGE; DRUG MECHANISM; EMBRYO; EMBRYO CELL; FEMALE; FIBROBLAST; FITNESS; GENE; GLUCOSE TOLERANCE; HEALTH; LIFESPAN; MOUSE; NONHUMAN; OSTEOPOROSIS; PRIORITY JOURNAL; SKIN FUNCTION; TELOMERE;

ANIMALS; ANTICARCINOGENIC AGENTS; ASTRAGALUS MEMBRANACEUS; DIET; DNA DAMAGE; EMBRYO, MAMMALIAN; FEMALE; FIBROBLASTS; MICE; MICE, INBRED C57BL; NEOPLASMS; RNA; TELOMERASE; TELOMERE;

ASTRAGALUS MEMBRANACEUS; MUS;

EID: 79960322707     PISSN: 14749718     EISSN: 14749726     Source Type: Journal    
DOI: 10.1111/j.1474-9726.2011.00700.x     Document Type: Article

References (84)

1. Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie M, Vulto I, Phillips JA 3rd, Lansdorp PM, Greider CW, Loyd JE (2007) Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 356, 1317-1326.
2. Artandi SE, Alson S, Tietze MK, Sharpless NE, Ye S, Greenberg RA, Castrillon DH, Horner JW, Weiler SR, Carrasco RD, DePinho RA (2002) Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc. Natl. Acad. Sci. USA 99, 8191-8196.
3. Au WS, Kung HF, Lin MC (2003) Regulation of microsomal triglyceride transfer protein gene by insulin in HepG2 cells: roles of MAPKerk and MAPKp38. Diabetes 52, 1073-1080.
4. Bailey CJ, Flatt PR (1982) Hormonal control of glucose homeostasis during development and ageing in mice. Metabolism 31, 238-246.
5. Berryman DE, Christiansen JS, Johannsson G, Thorner MO, Kopchick JJ (2008) Role of the GH/IGF-1 axis in lifespan and healthspan: lessons from animal models. Growth Horm. IGF Res. 18, 455-471.
6. Bianchi A, Shore D (2007) Increased association of telomerase with short telomeres in yeast. Genes Dev. 21, 1726-1730.
7. Blackburn EH (2001) Switching and signaling at the telomere. Cell 106, 661-673.
8. Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, Greider CW (1997) Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25-34.
9. Bluher M, Bashan N, Shai I, Harman-Boehm I, Tarnovscki T, Avinaoch E, Stumvoll M, Dietrich A, Kloting N, Rudich A (2009) Activated Ask1-MKK4-p38MAPK/JNK stress signaling pathway in human omental fat tissue may link macrophage infiltration to whole-body insulin sensitivity. J. Clin. Endocrinol. Metab. 94, 2507-2515.
10. Calado RT, Young NS (2009) Telomere diseases. N. Engl. J. Med. 361, 2353-2365.
11. Canela A, Martin-Caballero J, Flores JM, Blasco MA (2004) Constitutive expression of tert in thymocytes leads to increased incidence and dissemination of T-cell lymphoma in Lck-Tert mice. Mol. Cell. Biol. 24, 4275-4293.
12. Canela A, Vera E, Klatt P, Blasco MA (2007) High-throughput telomere length quantification by FISH and its application to human population studies. Proc. Natl. Acad. Sci. USA 104, 5300-5305.
13. Cayuela ML, Flores JM, Blasco MA (2005) The telomerase RNA component Terc is required for the tumour-promoting effects of Tert overexpression. EMBO Rep. 6, 268-274.
14. Cerezo A, Stark HJ, Moshir S, Boukamp P (2003) Constitutive overexpression of human telomerase reverse transcriptase but not c-myc blocks terminal differentiation in human HaCaT skin keratinocytes. J. Invest. Dermatol. 121, 110-119.
15. Chang L, Karin M (2001) Mammalian MAP kinase signalling cascades. Nature 410, 37-40.
16. Clement-Kruzel S, Hwang SA, Kruzel MC, Dasgupta A, Actor JK (2008) Immune modulation of macrophage pro-inflammatory response by goldenseal and Astragalus extracts. J. Med. Food. 11, 493-498.
17. Ewing KL, Tauber OE (1964) Hematological Changes in Aging Male C57bl/6 Jax Mice. J. Gerontol. 19, 165-167.
18. Fauce SR, Jamieson BD, Chin AC, Mitsuyasu RT, Parish ST, Ng HL, Kitchen CM, Yang OO, Harley CB, Effros RB (2008) Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes. J. Immunol. 181, 7400-7406.
19. Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, Gores GJ (2003) Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 125, 437-443.
20. Ferguson VL, Ayers RA, Bateman TA, Simske SJ (2003) Bone development and age-related bone loss in male C57BL/6J mice. Bone 33, 387-398.
21. Finch CE, Foster JR (1973) Hematologic and serum electrolyte values of the C57BL-6J male mouse in maturity and senescence. Lab. Anim. Sci. 23, 339-349.
22. Flores I, Cayuela ML, Blasco MA (2005) Effects of telomerase and telomere length on epidermal stem cell behavior. Science 309, 1253-1256.
23. Flores I, Canela A, Vera E, Tejera A, Cotsarelis G, Blasco MA (2008) The longest telomeres: a general signature of adult stem cell compartments. Genes Dev. 22, 654-667.
24. Gomez-Garcia L, Sanchez FM, Vallejo-Cremades MT, de Segura IA, del Campo Ede M (2005) Direct activation of telomerase by GH via phosphatidylinositol 3'-kinase. J. Endocrinol. 185, 421-428.
25. Gonzalez-Suarez E, Samper E, Ramirez A, Flores JM, Martin-Caballero J, Jorcano JL, Blasco MA (2001) Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO J. 20, 2619-2630.
26. Greenberg RA, O'Hagan RC, Deng H, Xiao Q, Hann SR, Adams RR, Lichtsteiner S, Chin L, Morin GB, DePinho RA (1999) Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation. Oncogene 18, 1219-1226.
27. Greider CW (1998) Telomerase activity, cell proliferation, and cancer. Proc. Natl. Acad. Sci. USA 95, 90-92.
28. Greider CW, Blackburn EH (1985) Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43, 405-413.
29. Guarente L (2006) Sirtuins as potential targets for metabolic syndrome. Nature 444, 868-874.
30. Guarente L, Kenyon C (2000) Genetic pathways that regulate ageing in model organisms. Nature 408, 255-262.
31. Gupta S, Seth A, Davis RJ (1993) Transactivation of gene expression by Myc is inhibited by mutation at the phosphorylation sites Thr-58 and Ser-62. Proc. Natl. Acad. Sci. USA 90, 3216-3220.
32. Hao LY, Armanios M, Strong MA, Karim B, Feldser DM, Huso D, Greider CW (2005) Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 123, 1121-1131.
33. Harley CB (2005) Telomerase therapeutics for degenerative diseases. Curr. Mol. Med. 5, 205-211.
34. Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345, 458-460.
35. Harley CB, Liu W, Blasco M, Vera E, Andrews WH, Briggs LA, Raffaele JM (2010) A natural product telomerase activator as part of a health maintenance program. Rejuvenation Res. 14, 45-56.
36. Hayflick L (2000) The future of ageing. Nature 408, 267-269.
37. Heikkinen S, Argmann CA, Champy MF, Auwerx J (2007) Evaluation of glucose homeostasis. Curr. Protoc. Mol. Biol. Chapter 29, Unit 29B 23.
38. Hemann MT, Rudolph KL, Strong MA, DePinho RA, Chin L, Greider CW (2001a) Telomere dysfunction triggers developmentally regulated germ cell apoptosis. Mol. Biol. Cell 12, 2023-2030.
39. Hemann MT, Strong MA, Hao LY, Greider CW (2001b) The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107, 67-77.
40. Herranz D, Serrano M (2010) Impact of Sirt1 on mammalian aging. Aging (Albany NY) 2, 315-316.
41. Herrera E, Samper E, Martin-Caballero J, Flores JM, Lee HW, Blasco MA (1999) Disease states associated with telomerase deficiency appear earlier in mice with short telomeres. EMBO J. 18, 2950-2960.
42. Higuchi H, Gores GJ (2003) Mechanisms of liver injury: an overview. Curr. Mol. Med. 3, 483-490.
43. Inui T, Shinomiya N, Fukasawa M, Kuranaga N, Ohkura S, Seki S (2001) Telomerase activation and MAPK pathways in regenerating hepatocytes. Hum. Cell 14, 275-282.
44. Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, Adams AC, Sahin E, Kost-Alimova M, Protopopov A, Cadinanos J, Horner JW, Maratos-Flier E, Depinho RA (2011) Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469, 102-106.
45. Jiang H, Schiffer E, Song Z, Wang J, Zurbig P, Thedieck K, Moes S, Bantel H, Saal N, Jantos J, Brecht M, Jeno P, Hall MN, Hager K, Manns MP, Hecker H, Ganser A, Dohner K, Bartke A, Meissner C, Mischak H, Ju Z, Rudolph KL (2008) Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease. Proc. Natl. Acad. Sci. USA 105, 11299-11304.
46. Kang SS, Kwon T, Kwon DY, Do SI (1999) Akt protein kinase enhances human telomerase activity through phosphorylation of telomerase reverse transcriptase subunit. J. Biol. Chem. 274, 13085-13090.
47. Kelder B, Boyce K, Kriete A, Clark R, Berryman DE, Nagatomi S, List EO, Braughler M, Kopchick JJ (2007) CIDE-A is expressed in liver of old mice and in type 2 diabetic mouse liver exhibiting steatosis. Comp. Hepatol. 6, 4.
48. Kenyon CJ (2010) The genetics of ageing. Nature 464, 504-512.
49. Kirkwood TB, Austad SN (2000) Why do we age? Nature 408, 233-238.
50. Kyriakis JM, Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol. Rev. 81, 807-869.
51. de Lange T (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 19, 2100-2110.
52. Lefloch R, Pouyssegur J, Lenormand P (2008) Single and combined silencing of ERK1 and ERK2 reveals their positive contribution to growth signaling depending on their expression levels. Mol. Cell. Biol. 28, 511-527.
53. Li G, Barrett EJ, Barrett MO, Cao W, Liu Z (2007) Tumor necrosis factor-alpha induces insulin resistance in endothelial cells via a p38 mitogen-activated protein kinase-dependent pathway. Endocrinology 148, 3356-3363.
54. Liu Y, Snow BE, Hande MP, Yeung D, Erdmann NJ, Wakeham A, Itie A, Siderovski DP, Lansdorp PM, Robinson MO, Harrington L (2000) The telomerase reverse transcriptase is limiting and necessary for telomerase function in vivo. Curr. Biol. 10, 1459-1462.
55. Mao XQ, Yu F, Wang N, Wu Y, Zou F, Wu K, Liu M, Ouyang JP (2009) Hypoglycemic effect of polysaccharide enriched extract of Astragalus membranaceus in diet induced insulin resistant C57BL/6J mice and its potential mechanism. Phytomedicine 16, 416-425.
56. Martinez P, Thanasoula M, Carlos AR, Gomez-Lopez G, Tejera AM, Schoeftner S, Dominguez O, Pisano DG, Tarsounas M, Blasco MA (2010) Mammalian Rap1 controls telomere function and gene expression through binding to telomeric and extratelomeric sites. Nat. Cell Biol. 12, 768-780.
57. Matheu A, Maraver A, Klatt P, Flores I, Garcia-Cao I, Borras C, Flores JM, Vina J, Blasco MA, Serrano M (2007) Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448, 375-379.
58. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412-419.
59. McIlrath J, Bouffler SD, Samper E, Cuthbert A, Wojcik A, Szumiel I, Bryant PE, Riches AC, Thompson A, Blasco MA, Newbold RF, Slijepcevic P (2001) Telomere length abnormalities in mammalian radiosensitive cells. Cancer Res. 61, 912-915.
60. McKay JD, Hung RJ, Gaborieau V, Boffetta P, Chabrier A, Byrnes G, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, McLaughlin J, Shepherd F, Montpetit A, Narod S, Krokan HE, Skorpen F, Elvestad MB, Vatten L, Njolstad I, Axelsson T, Chen C, Goodman G, Barnett M, Loomis MM, Lubinski J, Matyjasik J, Lener M, Oszutowska D, Field J, Liloglou T, Xinarianos G, Cassidy A, Vineis P, Clavel-Chapelon F, Palli D, Tumino R, Krogh V, Panico S, Gonzalez CA, Ramon Quiros J, Martinez C, Navarro C, Ardanaz E, Larranaga N, Kham KT, Key T, Bueno-de-Mesquita HB, Peeters PH, Trichopoulou A, Linseisen J, Boeing H, Hallmans G, Overvad K, Tjonneland A, Kumle M, Riboli E, Zelenika D, Boland A, Delepine M, Foglio M, Lechner D, Matsuda F, Blanche H, Gut I, Heath S, Lathrop M, Brennan P (2008) Lung cancer susceptibility locus at 5p15.33. Nat. Genet. 40, 1404-1406.
61. Mitchell JR, Wood E, Collins K (1999) A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402, 551-555.
62. Moynihan KA, Grimm AA, Plueger MM, Bernal-Mizrachi E, Ford E, Cras-Meneur C, Permutt MA, Imai S (2005) Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell Metab. 2, 105-117.
63. Park JI, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M, Chang W, Meng Z, Cheung P, Ji H, McLaughlin M, Veenstra TD, Nusse R, McCrea PD, Artandi SE (2009) Telomerase modulates Wnt signalling by association with target gene chromatin. Nature 460, 66-72.
64. Pericuesta E, Ramirez MA, Villa-Diaz A, Relano-Gines A, Torres JM, Nieto M, Pintado B, Gutierrez-Adan A (2006) The proximal promoter region of mTERT is sufficient to regulate telomerase activity in ES cells and transgenic animals. Reprod. Biol. Endocrinol. 4, 5.
65. Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tschop MH (2008) Sirt1 protects against high-fat diet-induced metabolic damage. Proc. Natl. Acad. Sci. USA 105, 9793-9798.
66. Rafnar T, Sulem P, Stacey SN, Geller F, Gudmundsson J, Sigurdsson A, Jakobsdottir M, Helgadottir H, Thorlacius S, Aben KK, Blondal T, Thorgeirsson TE, Thorleifsson G, Kristjansson K, Thorisdottir K, Ragnarsson R, Sigurgeirsson B, Skuladottir H, Gudbjartsson T, Isaksson HJ, Einarsson GV, Benediktsdottir KR, Agnarsson BA, Olafsson K, Salvarsdottir A, Bjarnason H, Asgeirsdottir M, Kristinsson KT, Matthiasdottir S, Sveinsdottir SG, Polidoro S, Hoiom V, Botella-Estrada R, Hemminki K, Rudnai P, Bishop DT, Campagna M, Kellen E, Zeegers MP, de Verdier P, Ferrer A, Isla D, Vidal MJ, Andres R, Saez B, Juberias P, Banzo J, Navarrete S, Tres A, Kan D, Lindblom A, Gurzau E, Koppova K, de Vegt F, Schalken JA, van der Heijden HF, Smit HJ, Termeer RA, Oosterwijk E, van Hooij O, Nagore E, Porru S, Steineck G, Hansson J, Buntinx F, Catalona WJ, Matullo G, Vineis P, Kiltie AE, Mayordomo JI, Kumar R, Kiemeney LA, Frigge ML, Jonsson T, Saemundsson H, Barkardottir RB, Jonsson E, Jonsson S, Olafsson JH, Gulcher JR, Masson G, Gudbjartsson DF, Kong A, Thorsteinsdottir U, Stefansson K (2009) Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nat. Genet. 41, 221-227.
67. Sabourin M, Tuzon CT, Zakian VA (2007) Telomerase and Tel1p preferentially associate with short telomeres in S. cerevisiae. Mol. Cell 27, 550-561.
68. Samper E, Goytisolo FA, Slijepcevic P, van Buul PP, Blasco MA (2000) Mammalian Ku86 protein prevents telomeric fusions independently of the length of TTAGGG repeats and the G-strand overhang. EMBO Rep. 1, 244-252.
69. -/- mice with short telomeres. EMBO Rep. 2, 800-807.
70. Shen P, Liu MH, Ng TY, Chan YH, Yong EL (2006) Differential effects of isoflavones, from Astragalus membranaceus and Pueraria thomsonii, on the activation of PPARalpha, PPARgamma, and adipocyte differentiation in vitro. J. Nutr. 136, 899-905.
71. Shimokata H, Tobin JD, Muller DC, Elahi D, Coon PJ, Andres R (1989) Studies in the distribution of body fat: I. Effects of age, sex, and obesity. J. Gerontol. 44, M66-M73.
72. Siegl-Cachedenier I, Flores I, Klatt P, Blasco MA (2007) Telomerase reverses epidermal hair follicle stem cell defects and loss of long-term survival associated with critically short telomeres. J. Cell Biol. 179, 277-290.
73. Takakura M, Kyo S, Inoue M, Wright WE, Shay JW (2005) Function of AP-1 in transcription of the telomerase reverse transcriptase gene (TERT) in human and mouse cells. Mol. Cell. Biol. 25, 8037-8043.
74. Teixeira MT, Arneric M, Sperisen P, Lingner J (2004) Telomere length homeostasis is achieved via a switch between telomerase- extendible and -nonextendible states. Cell 117, 323-335.
75. Tomas-Loba A, Flores I, Fernandez-Marcos PJ, Cayuela ML, Maraver A, Tejera A, Borras C, Matheu A, Klatt P, Flores JM, Vina J, Serrano M, Blasco MA (2008) Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell 135, 609-622.
76. Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, Rosenblatt RL, Shay JW, Garcia CK (2007) Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc. Natl. Acad. Sci. USA 104, 7552-7557.
77. Tyan ML (1980) Marrow colony-forming units: age-related changes in responses to anti-theta-sensitive helper/suppressor stimuli. Proc. Soc. Exp. Biol. Med. 165, 354-360.
78. Tyan ML (1982a) Age-related increase in erythrocyte oxidant sensitivity. Mech. Ageing Dev. 20, 25-32.
79. Tyan ML (1982b) Effect of age on the intrinsic regulation of murine hemopoiesis. Mech. Ageing Dev. 19, 15-20.
80. Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M, Mason PJ, Dokal I (2001) The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413, 432-435.
81. Wang J, Xie LY, Allan S, Beach D, Hannon GJ (1998) Myc activates telomerase. Genes Dev. 12, 1769-1774.
82. Xing Z, Ryan MA, Daria D, Nattamai KJ, Van Zant G, Wang L, Zheng Y, Geiger H (2006) Increased hematopoietic stem cell mobilization in aged mice. Blood 108, 2190-2197.
83. Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, Lansdorp PM, Young NS (2005) Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl. J. Med. 352, 1413-1424.
84. Yuan JS, Reed A, Chen F, Stewart CN Jr (2006) Statistical analysis of real-time PCR data. BMC Bioinformatics 7, 85.