Abstract
Chronological aging of the yeast Saccharomyces cerevisiae is attributed to multi-faceted traits especially those involving genome instability, and has been considered to be an aging model for post-mitotic cells in higher organisms. Telomeres are the physical ends of eukaryotic chromosomes, and are essential for genome integrity and stability. It remains elusive whether dysregulated telomerase activity affects chronological aging. We employed the CDC13-EST2 fusion gene, which tethers telomerase to telomeres, to examine the effect of constitutively active telomerase on chronological lifespan (CLS). The expression of Cdc13-Est2 fusion protein resulted in overlong telomeres (2 to 4 folds longer than normal telomeres), and long telomeres were stably maintained during long-term chronological aging. Accordingly, genome instability, manifested by accumulation of extra-chromosomal rDNA circle species, age-dependent CAN1 marker-gene mutation frequency and gross chromosomal rearrangement frequency, was significantly elevated. Importantly, inactivation of Sch9, a downstream kinase of the target of rapamycin complex 1 (TORC1), suppressed both the genome instability and accelerated chronological aging mediated by CDC13-EST2 expression. Interestingly, loss of the CDC13-EST2 fusion gene in the cells with overlong telomeres restored the regular CLS. Altogether, these data suggest that constitutively active telomerase is detrimental to the maintenance of genome stability, and promotes chronological aging in yeast.
Highlights
Aging is broadly defined as a time-dependent functional decline that most living organisms seem to be unable to escape
The expression of Cdc13‐Est2 fusion protein resulted in overlong telomeres (2 to 4 folds longer than normal telomeres), and long telomeres were stably maintained during long‐term chronological aging
Inactivation of Sch9, a downstream kinase of the target of rapamycin complex 1 (TORC1), suppressed both the genome instability and accelerated chronological aging mediated by CDC13‐EST2 expression
Summary
Aging is broadly defined as a time-dependent functional decline that most living organisms seem to be unable to escape It is one of the leading risk factors for a number of aging-associated diseases including atherosclerosis, type 2 diabetes, cardiovascular diseases, cancer and Alzheimer's disease [1]. Two evolutionarily conserved nutrient-sensing signaling pathways, the Tor (target of rapamycin )/Sch pathway www.aging‐us.com and Ras/PKA pathway, are first demonstrated to modulate CLS in the budding yeast S. cerevisiae [14]. These two signaling pathways are later found to regulate lifespan in higher organisms including mammals as well [2, 15,16,17,18]. The evolutionarily conserved Tor/Sch pathway and Ras/PKA pathway regulate replicative aging [4, 20]
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