Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc(-/-) mice with short telomeres

Reconstitution of telomerase activity is proposed as a potential gene thera py to prevent, or rescue, age-related diseases produced by critical telomer e shortening. However, it is not known whether or not short telomeres are i rreversibly damaged. We addressed this by re-introducing telomerase in late generation telomerase-deficient mice, Terc(-/-), which have short telomere s and show severe proliferative defects. For this, we have crossed these mi ce with Terc(+/-) mice and analyzed telomere length, chromosomal instabilit y and premature aging of the progeny. The Terc(-/-) progeny had one set of chromosomes with normal telomeres, whereas the other set remained with crit ically short telomeres; these mice presented chromosomal instability and pr emature aging. In contrast, Terc(+/-) progeny showed all chromosomes with d etectable telomeres, and did not show chromosomal instability or premature aging. These results prove that critically short telomeres can be rescued b y telomerase, and become fully functional, thus rescuing premature aging. T his has important implications for the future design of telomerase-based ge ne therapy,of age-related diseases.