Stochastic Variation in Telomere Shortening Rate Causes Heterogeneity of Human Fibroblast Replicative Life Span

Telomere shortening to a critical length can trigger aging and shorter life spans in mice and humans by a mechanism that involves induction of a persistent DNA damage response at chromosome ends and loss of cellular viability. However, whether telomere length is a universal determinant of species longevity is not known. To determine whether telomere shortening can be a single parameter to predict species longevities, here we measured in parallel the telomere length of a wide variety of species (birds and mammals) with very different life spans and body sizes, including mouse (Mus musculus), goat (Capra hircus), Audouin’s gull (Larus audouinii), reindeer (Rangifer tarandus), griffon vulture (Gyps fulvus), bottlenose dolphin (Tursiops truncatus), American flamingo (Phoenicopterus ruber), and Sumatran elephant (Elephas maximus sumatranus). We found that the telomere shortening rate, but not the initial telomere length alone, is a powerful predictor of species life span. These results support the notion that critical telomere shortening and the consequent onset of telomeric DNA damage and cellular senescence are a general determinant of species life span.

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On the correlation between telomere shortening rate and life span

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1920300117 ◽

2020 ◽

Vol 117 (5) ◽

pp. 2248-2249 ◽

Cited By ~ 3

Author(s):

Ion Udroiu

Keyword(s):

Life Span ◽

Telomere Shortening ◽

Shortening Rate

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FOXO3a Potentiates hTERT Gene Expression by Activating c-MYC and Extends the Replicative Life-Span of Human Fibroblast

PLoS ONE ◽

10.1371/journal.pone.0101864 ◽

2014 ◽

Vol 9 (7) ◽

pp. e101864 ◽

Cited By ~ 19

Author(s):

Shuntaro Yamashita ◽

Kaori Ogawa ◽

Takahiro Ikei ◽

Tsukasa Fujiki ◽

Yoshinori Katakura

Keyword(s):

Gene Expression ◽

Life Span ◽

Human Fibroblast ◽

Replicative Life Span ◽

Htert Gene

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Telomerase Alone Extends the Replicative Life Span of Human Skeletal Muscle Cells Without Compromising Genomic Stability

Human Gene Therapy ◽

10.1089/104303403769211682 ◽

2003 ◽

Vol 14 (15) ◽

pp. 1473-1487 ◽

Cited By ~ 24

Author(s):

Martha Wootton ◽

Karen Steeghs ◽

Diana Watt ◽

June Munro ◽

Katrina Gordon ◽

...

Keyword(s):

Skeletal Muscle ◽

Life Span ◽

Human Skeletal Muscle ◽

Genomic Stability ◽

Muscle Cells ◽

Skeletal Muscle Cells ◽

Replicative Life Span ◽

Human Skeletal Muscle Cells

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Loss of Ubp3 increases silencing, decreases unequal recombination in rDNA, and shortens the replicative life span in Saccharomyces cerevisiae

Molecular Biology of the Cell ◽

10.1091/mbc.e13-10-0591 ◽

2014 ◽

Vol 25 (12) ◽

pp. 1916-1924 ◽

Cited By ~ 3

Author(s):

David Öling ◽

Rehan Masoom ◽

Kristian Kvint

Keyword(s):

Saccharomyces Cerevisiae ◽

Rna Polymerase ◽

Life Span ◽

Rna Polymerase Ii ◽

Ribosomal Dna ◽

Genetic Evidence ◽

Wild Type ◽

Replicative Life Span ◽

Unequal Recombination

Ubp3 is a conserved ubiquitin protease that acts as an antisilencing factor in MAT and telomeric regions. Here we show that ubp3∆ mutants also display increased silencing in ribosomal DNA (rDNA). Consistent with this, RNA polymerase II occupancy is lower in cells lacking Ubp3 than in wild-type cells in all heterochromatic regions. Moreover, in a ubp3∆ mutant, unequal recombination in rDNA is highly suppressed. We present genetic evidence that this effect on rDNA recombination, but not silencing, is entirely dependent on the silencing factor Sir2. Further, ubp3∆ sir2∆ mutants age prematurely at the same rate as sir2∆ mutants. Thus our data suggest that recombination negatively influences replicative life span more so than silencing. However, in ubp3∆ mutants, recombination is not a prerequisite for aging, since cells lacking Ubp3 have a shorter life span than isogenic wild-type cells. We discuss the data in view of different models on how silencing and unequal recombination affect replicative life span and the role of Ubp3 in these processes.

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