DAF-16 and PQM-1: Partners in longevity

Tepper, Ronald G.; Murphy, Coleen T.; Bussemaker, Harmen J.

doi:10.18632/aging.100628

Cited by 6 publications

(9 citation statements)

References 9 publications

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“…elegans , WormExp 31 ; a high-quality protein-DNA interaction network 32 ; and two databases of miRNA-target interactions: the in silico predicted TargetScan 33 and the experimentally validated MirTarBase 34 . Enrichment analysis of the list detected ten hits already experimentally characterised as regulators of aging: DAF-16 35 , ELT-2 36 , ELT-6 37 , PMK-1 38,39 , PQM-1 40 , NHR-1, NHR-10, NHR-86 41 , let -7 42,43 , and miR-60 44 .…”

Section: Resultsmentioning

confidence: 99%

A universal transcriptomic signature of age reveals the temporal scaling of Caenorhabditis elegans aging trajectories

Tarkhov

Alla

Ayyadevara

et al. 2019

Sci Rep

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We collected 60 age-dependent transcriptomes for C. elegans strains including four exceptionally long-lived mutants (mean adult lifespan extended 2.2- to 9.4-fold) and three examples of lifespan-increasing RNAi treatments. Principal Component Analysis (PCA) reveals aging as a transcriptomic drift along a single direction, consistent across the vastly diverse biological conditions and coinciding with the first principal component, a hallmark of the criticality of the underlying gene regulatory network. We therefore expected that the organism’s aging state could be characterized by a single number closely related to vitality deficit or biological age. The “aging trajectory”, i.e. the dependence of the biological age on chronological age, is then a universal stochastic function modulated by the network stiffness; a macroscopic parameter reflecting the network topology and associated with the rate of aging. To corroborate this view, we used publicly available datasets to define a transcriptomic biomarker of age and observed that the rescaling of age by lifespan simultaneously brings together aging trajectories of transcription and survival curves. In accordance with the theoretical prediction, the limiting mortality value at the plateau agrees closely with the mortality rate doubling exponent estimated at the cross-over age near the average lifespan. Finally, we used the transcriptomic signature of age to identify possible life-extending drug compounds and successfully tested a handful of the top-ranking molecules in C. elegans survival assays and achieved up to a +30% extension of mean lifespan.

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Section: Resultsmentioning

confidence: 99%

A universal transcriptomic signature of age reveals the temporal scaling of Caenorhabditis elegans aging trajectories

Tarkhov

Alla

Ayyadevara

et al. 2019

Sci Rep

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“…We further employed the Worm Exp tool (https://wormexp.zoologie.uni-kiel.de/wormexp/) (Yang et al, 2016) to analyze the age determination genes to identify specific pathways that could be transcriptionally regulated by PITX/UNC-30. We found that the SKN-1, MDL-1, and PQM-1 age determination pathways were highly enriched (Figure 2D and Table S4) (Riesen et al, 2014; Tepper et al, 2013a; Tepper et al, 2014; Tullet et al, 2008). Although the SKN-1 cluster had the highest representation factor (Figure 2D), most of the genes up-regulated in unc-30(ok613) animals were under the control of the MDL-1 pathway (Figure 2E).…”

Section: Resultsmentioning

confidence: 96%

“…Although the SKN-1 cluster had the highest representation factor (Figure 2D), most of the genes up-regulated in unc-30(ok613) animals were under the control of the MDL-1 pathway (Figure 2E). Because the evolutionarily conserved transcription factors, MDL-1 and PQM-1 are known to suppress longevity and their inactivation results in lifespan extension (Riesen et al, 2014; Tepper et al, 2013b; Tepper et al, 2014), the upregulation of MDL-1 and PQM-1-dependent genes in unc-30(ok613) animals could explain the reduced longevity of the animals. We confirmed the role of PITX/UNC-30 in the control of MDL-1 and PQM-1-dependent genes (Figure 2F).…”

Section: Resultsmentioning

confidence: 99%

“…While PITX/UNC-30 suppresses immunity by inhibiting GATA/ELT-2-and p38 MAPK/PMK-1-dependent genes, it enhances longevity by inhibiting the MXD/MDL-1 and PQM-1. Functional loss of MDL-1 and PQM-1 extends lifespan in C. elegans via DAF-2 insulin/IGF-1 (Johnson et al, 2014; Nakamura et al, 2016; Riesen et al, 2014; Templeman et al, 2018; Tepper et al, 2013b; Tepper et al, 2014). In addition, PQM-1 functions together with DAF-16 as a key transcriptional regulator of DAF-2-mediated longevity (Tepper et al, 2013b).…”

Section: Discussionmentioning

confidence: 99%

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Immunity-longevity tradeoff neurally controlled by GABAergic transcription factor PITX1/UNC-30

Otarigho

Aballay

2021

Preprint

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A body of evidence indicates that metazoan immune and aging pathways are largely interconnected, but the mechanisms involved in their homeostatic control remain unclear. In this study, we found that the PITX (paired like homeodomain) transcription factor UNC-30 controls the tradeoff between immunity and longevity from the nervous system in Caenorhabditis elegans. PITX/UNC-30 functional loss enhanced immunity in a GATA/ELT-2- and p38 MAPK/PMK-1-dependent manner and reduced longevity by activating the MXD/MDL-1 and PQM-1 pathways. The immune inhibitory and longevity stimulatory functions of PITX/UNC-30 required the sensory neuron ASG and a neurotransmitter signaling pathway controlled by NPR-1, which is a G protein-coupled receptor related to mammalian neuropeptide Y receptors. Our findings uncovered a suppressive role of GABAergic signaling in the neural control of a biological tradeoff where energy is allocated towards immunity at the expense of longevity.

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“…We found enrichment for genes encoding protein targets of PMK-1 (p38 mitogen-activated protein kinase, a regulator of the innate immune response), reported to contribute to longevity and immunosenescence [35,45], and PQM-1, a stress-response transcription factor that interacts antagonistically with DAF-16, recently characterized as an important lifespan regulator [46].…”

Section: Targets Of Transcription Factors or Rna Binding Proteinsmentioning

confidence: 98%

Universal transcriptomic signature of age reveals temporal scaling ofCaenorhabditis elegansaging trajectories

Tarkhov

Alla

Ayyadevara

et al. 2017

Preprint

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To detect overlap or convergence among the diverse genetic pathways that can extend lifespan, we collected a dataset of 60 C.elegans age-dependent transcriptomes by RNA-seq technique for worm strains with vastly different lifespans. We selected four exceptionally long-lived mutants and three examples of the most successful life-extending RNAi treatments (which increased mean lifespan by 35% rather than 120% as reported). We used the dataset augmented with publicly available gene expression datasets to produce a transcriptomic signature of biological age. We introduced a transcriptomic measure of biological age and observed that its dependence on chronological age is modulated by a single parameter, the rate of aging. We hypothesized that the scaling revealed in the gene expression kinetics underlies the recently observed scaling of the survival curves in C.elegans, and the stochasticity in gene expressions leads to deceleration of mortality with age, reaching a plateau at advanced ages. Using experimental survival data, we confirm that the plateau mortality agrees closely with the estimate of Gompertz exponent at the cross-over age near the mean lifespan. The genes associated with aging in our data are enriched with the targets of transcription factors such as DAF-16, ELT-2, ELT-6, NHR-10, ZTF-9, NHR-86, and miRNAs including miR-57, -59, and -244, which is in agreement with previous studies. Overall, our meta-analysis results are consistent with a concept of aging based on critical dynamics of molecular level variables (e.g., gene expression), and support our view of aging as arising from dynamic instability of a single (critical) mode.

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DAF-16 and PQM-1: Partners in longevity

Cited by 6 publications

References 9 publications

A universal transcriptomic signature of age reveals the temporal scaling of Caenorhabditis elegans aging trajectories

A universal transcriptomic signature of age reveals the temporal scaling of Caenorhabditis elegans aging trajectories

Immunity-longevity tradeoff neurally controlled by GABAergic transcription factor PITX1/UNC-30

Universal transcriptomic signature of age reveals temporal scaling ofCaenorhabditis elegansaging trajectories

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