The Length of the Shortest Telomere as the Major Determinant of the Onset of Replicative Senescence

Abstract

The absence of telomerase in many eukaryotes leads to the gradual shortening of telomeres, causing replicative senescence. In humans, this proliferation barrier constitutes a tumor suppressor mechanism and may be involved in cellular aging. Yet the heterogeneity of the senescence phenotype has hindered the understanding of its onset. Here we investigated the regulation of telomere length and its control of senescence heterogeneity. Because the length of the shortest telomeres can potentially regulate cell fate, we focus on their dynamics in Saccharomyces cerevisiae. We developed a stochastic model of telomere dynamics built on the protein-counting model, where an increasing number of protein-bound telomeric repeats shift telomeres into a nonextendable state by telomerase. Using numerical simulations, we found that the length of the shortest telomere is well separated from the length of the others, suggesting a prominent role in triggering senescence. We evaluated this possibility using classical genetic analyses of tetrads, combined with a quantitative and sensitive assay for senescence. In contrast to mitosis of telomerase-negative cells, which produces two cells with identical senescence onset, meiosis is able to segregate a determinant of senescence onset among the telomerase-negative spores. The frequency of such segregation is in accordance with this determinant being the length of the shortest telomere. Taken together, our results substantiate the length of the shortest telomere as being the key genetic marker determining senescence onset in S. cerevisiae.

Length-dependent processing of telomeres in the absence of telomerase

“…We demonstrated using formal genetic analysis that the onset of senescence is determined by a single dominant telomere in budding yeast, likely the shortest one (67). Accordingly, generating a single artificial very short telomere accelerates the onset of senescence (33).…”

Aging of intrauterine tissues in spontaneous preterm birth and preterm premature rupture of the membranes: A systematic review of the literature

“…Few studies have investigated the association between adverse pregnancy outcomes (APOs) and placental aging and/or oxidative stress [16e19]. The most studied aging biomarker is the reduction of telomeres, the nucleotide sequences that caps the end of the chromosome and protects it from damage [20]. Shorter telomeres have been reported in trophoblasts from pregnancies with preeclampsia and intrauterine growth restriction, compared to uncomplicated pregnancies [16].…”

The many types of heterogeneity in replicative senescence

“…When a pair of telomerase‐negative mother and daughter cells are separated by micromanipulation and grown independently, minor differences in proliferation potential between the two resulting cultures are observed (Xu, Duc, Holcman, & Teixeira, ). They are, however, much smaller than the differences observed between pairs of telomerase‐negative spores of the same tetrad (Figure a,b).…”