Uncoupling of Longevity and Telomere Length in C. elegans

Raı́ces, Marcela; Maruyama, Hugo; Dillin, Andrew; Karlseder, Jan

doi:10.1371/journal.pgen.0010030

Cited by 63 publications

(44 citation statements)

References 29 publications

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“…Daf-16 RNAi also decreased lifespan in the mutant overexpressor animals, but this reduction was much less pronounced and mimicked the one observed in wild-type animals. A small negative effect of daf-16 RNAi on lifespan in N2 animals has been reported previously [40], [41]. Our results thus indicate that the PCM-1 isoaspartyl methyltransferase extends lifespan at 25°C at least partially by directly or indirectly downregulating the IIS pathway and thereby promoting nuclear translocation of DAF-16 with concomitant up-regulation of target genes promoting survival under mild thermal stress (Figure 5).…”

Section: Discussionsupporting

confidence: 82%

The Interplay between Protein L-Isoaspartyl Methyltransferase Activity and Insulin-Like Signaling to Extend Lifespan in Caenorhabditis elegans

2011

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The protein L-isoaspartyl-O-methyltransferase functions to initiate the repair of isomerized aspartyl and asparaginyl residues that spontaneously accumulate with age in a variety of organisms. Caenorhabditis elegans nematodes lacking the pcm-1 gene encoding this enzyme display a normal lifespan and phenotype under standard laboratory growth conditions. However, significant defects in development, egg laying, dauer survival, and autophagy have been observed in pcm-1 mutant nematodes when deprived of food and when exposed to oxidative stress. Interestingly, overexpression of this repair enzyme in both Drosophila and C. elegans extends adult lifespan under thermal stress. In this work, we show the involvement of the insulin/insulin-like growth factor-1 signaling (IIS) pathway in PCM-1-dependent lifespan extension in C. elegans. We demonstrate that reducing the levels of the DAF-16 downstream transcriptional effector of the IIS pathway by RNA interference reduces the lifespan extension resulting from PCM-1 overexpression. Using quantitative real-time PCR analysis, we show the up-regulation of DAF-16-dependent stress response genes in the PCM-1 overexpressor animals compared to wild-type and pcm-1 mutant nematodes under mild thermal stress conditions. Additionally, similar to other long-lived C. elegans mutants in the IIS pathway, including daf-2 and age-1 mutants, PCM-1 overexpressor adult animals display increased resistance to severe thermal stress, whereas pcm-1 mutant animals survive less long under these conditions. Although we observe a higher accumulation of damaged proteins in pcm-1 mutant nematodes, the basal level of isoaspartyl residues detected in wild-type animals was not reduced by PCM-1 overexpression. Our results support a signaling role for the protein L-isoaspartyl methyltransferase in lifespan extension that involves the IIS pathway, but that may be independent of its function in overall protein repair.

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Section: Discussionsupporting

confidence: 82%

The Interplay between Protein L-Isoaspartyl Methyltransferase Activity and Insulin-Like Signaling to Extend Lifespan in Caenorhabditis elegans

2011

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“…However, our cross‐sectional analyses did not reveal any association between TL and lizard survival, and hence, our results mirror those obtained by, for example, Raices et al . (), Hartmann et al . (), Ujvari & Madsen () and Schumpert et al .…”

Section: Discussionmentioning

confidence: 95%

“…) whereas other studies have failed to detect such associations in C. elegans (Raices et al . ), Daphnia spp. (Schumpert et al .…”

Section: Introductionmentioning

confidence: 99%

Curvilinear telomere length dynamics in a squamate reptile

et al. 2016

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Summary The lack of consensus concerning the impact of telomere length (TL) dynamics on survival emphasizes the need for additional studies to evaluate the effect of TL on key life‐history processes. Using both cross‐sectional and longitudinal data, we therefore explored age‐specific TL dynamics in a squamate reptile: the frillneck lizard (Chlamydosaurus kingii). Our cross‐sectional analyses revealed that young lizards had short TL, TL increased in medium‐aged lizards, but TL decreased in older age cohorts, revealing a curvilinear relationship between TL and frillneck lizard age. Neither our cross‐sectional nor our longitudinal analyses revealed any association between TL dynamics and lizard survival. We observed a significant positive relationship between TL and telomerase expression (TE), suggesting that TE is a significant determinant of frillneck lizard TL dynamics. Importantly, our longitudinal analyses revealed a positive relationship between initial TL and telomere attrition rate within individual lizards, that is lizards with short initial telomeres were subjected to reduced telomere attrition rates compared to lizards with long initial TL. Our results strongly suggest that TL and TE dynamics in frillneck lizards is not associated with lizard survival but rather reflect an adaptation to maintain TL above a critical minimum length in order to sustain cellular homeostasis. A http://onlinelibrary.wiley.com/doi/10.1111/1365-2435.12764/suppinfo is available for this article.

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“…Cellular models have been extremely helpful to understand telomerase biology and pathologies (Batista and Artandi, 2013), but they cannot easily recapitulate systemic defects or tissue interactions. Invertebrate models, which have provided crucial insights into telomerase function (Raices et al, 2005), lack some of the organs affected by telomere pathologies in humans (e.g. bona fide blood) (Gomes et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

A Platform for Rapid Exploration of Aging and Diseases in a Naturally Short-Lived Vertebrate

Harel

Benayoun

Machado

et al. 2015

Cell

210

198

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Summary Aging is a complex process that affects multiple organs. Modeling aging and age-related diseases in the lab is challenging because classical vertebrate models have relatively long lifespans. Here we develop the first platform for rapid exploration of age-dependent traits and diseases in vertebrates, using the naturally short-lived African turquoise killifish. We provide an integrative genomic and genome-editing toolkit in this organism using our de novo-assembled genome and the CRISPR/Cas9 technology. We mutate many genes encompassing the hallmarks of aging, and for a subset, we produce stable lines within 2–3 months. As a proof-of-principle, we show that fish deficient for the protein subunit of telomerase exhibit the fastest onset of telomere-related pathologies among vertebrates. We further demonstrate the feasibility of creating specific genetic variants. This genome-to-phenotype platform represents a unique resource for studying vertebrate aging and disease in a high throughput manner and for investigating candidates arising from human genome-wide studies.

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Uncoupling of Longevity and Telomere Length in C. elegans

Cited by 63 publications

References 29 publications

The Interplay between Protein L-Isoaspartyl Methyltransferase Activity and Insulin-Like Signaling to Extend Lifespan in Caenorhabditis elegans

The Interplay between Protein L-Isoaspartyl Methyltransferase Activity and Insulin-Like Signaling to Extend Lifespan in Caenorhabditis elegans

Curvilinear telomere length dynamics in a squamate reptile

A Platform for Rapid Exploration of Aging and Diseases in a Naturally Short-Lived Vertebrate

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