Unknown,Transcriptomics,Genomics,Proteomics

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Suppression of Transcriptional Drift Extends C. elegans Lifespan by Postponing the Onset of Mortality

ABSTRACT: Longevity mechanisms increase lifespan by counteracting the effects of aging. However, whether longevity mechanisms counteract the effects of aging continually throughout life, or whether they act during specific periods of life, preventing changes that precede mortality is unclear. Here, we uncover transcriptional drift, a phenomenon that describes how aging causes genes within functional groups to change expression in opposing directions. These changes cause a transcriptome-wide loss in mRNA stoichiometry and loss of co-expression patterns in aging animals, as compared to young adults. Using Caenorhabditis elegans as a model, we show that extending lifespan by inhibiting serotonergic signals by the antidepressant mianserin attenuates transcriptional drift, allowing the preservation of a younger transcriptome into an older age. Our data are consistent with a model in which inhibition of serotonergic signals slows age-dependent physiological decline and the associated rise in mortality levels exclusively in young adults, thereby postponing the onset of major mortality. In this study set out to measure aging in the transcriptome by determining drift-variance changes with age in C.elegans. We set up three different cohorts of water or mianserin treated animals. The title of each cohort indicates the treatment (e.g. h2o or mia), the concentration (mia2, mia10, mia50), the day when the treatment was started (e.g. d1= day 1 of adulthood) and the day when the sample was collected (e.g. d10= day 10 of adulthood). cohort #1: Celegans was treated with water or mianserin (50uM) on day 1 and RNA was harvested on day1 (water only), d3, d5 and day 10 (file titles: h2o d1/d1, h2o d1/d3, h2o d1/d5, h2o d1/d10, mia50 d1/d3, mia50 d1/d5, mia50 d1/d10) cohort #2: Celegans was treated with mianserin (50uM) starting on day 3, and day 5, RNA was harvested on day 5 or 10 (file titles: mia50 d3/d10, mia50 d5/d10, mia50 d3/d5) cohort #3: Celegans was treated with mianserin 2 uM and 10 uM Mianserin on day 1 and Rna harvested on day 5 (file titles: mia2 d1/d5, mia10 d1/d5)

ORGANISM(S): Caenorhabditis elegans

SUBMITTER: Michael Petrascheck

PROVIDER: E-GEOD-63528 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Suppression of transcriptional drift extends C. elegans lifespan by postponing the onset of mortality.

Rangaraju Sunitha S Solis Gregory M GM Thompson Ryan C RC Gomez-Amaro Rafael L RL Kurian Leo L Encalada Sandra E SE Niculescu Alexander B AB Salomon Daniel R DR Petrascheck Michael M

eLife 20151201

Longevity mechanisms increase lifespan by counteracting the effects of aging. However, whether longevity mechanisms counteract the effects of aging continually throughout life, or whether they act during specific periods of life, preventing changes that precede mortality is unclear. Here, we uncover transcriptional drift, a phenomenon that describes how aging causes genes within functional groups to change expression in opposing directions. These changes cause a transcriptome-wide loss in mRNA s ...[more]

PMID: 26623667

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Project description:MAPK cascade in solution (no scaffold) Description This model describes a basic 3- stage Mitogen Activated Protein Kinase (MAPK) cascade in solution. This cascade is typically expressed as RAF= =>MEK==>MAPK (alternative forms are K3==>K2==> K1 and KKK==>KK==>K) . The input signal is RAFK (RAF Kinase) and the output signal is MAPKpp ( doubly phosphorylated form of MAPK) . RAFK phosphorylates RAF once to RAFp. RAFp, the phosphorylated form of RAF induces two phoshporylations of MEK, to MEKp and MEKpp. MEKpp, the doubly phosphorylated form of MEK, induces two phosphorylations of MAPK to MAPKp and MAPKpp. Rate constant Reaction a10 = 5. MAPKPH + MAPKpp -> MAPKppMAPKPH a1 = 1. RAF + RAFK -> RAFRAFK a2 = 0.5 RAFp + RAFPH -> RAFpRAFPH a3 = 3.3 MEK + RAFp -> MEKRAFp a4 = 10. MEKp + MEKPH -> MEKpMEKPH a5 = 3.3 MEKp + RAFp -> MEKpRAFp a6 = 10. MEKPH + MEKpp -> MEKppMEKPH a7 = 20. MAPK + MEKpp -> MAPKMEKpp a8 = 5. MAPKp + MAPKPH -> MAPKpMAPKPH a9 = 20. MAPKp + MEKpp -> MAPKpMEKpp d10 = 0.4 MAPKppMAPKPH -> MAPKPH + MAPKpp d1 = 0.4 RAFRAFK -> RAF + RAFK d2 = 0.5 RAFpRAFPH -> RAFp + RAFPH d3 = 0.42 MEKRAFp -> MEK + RAFp d4 = 0.8 MEKpMEKPH -> MEKp + MEKPH d5 = 0.4 MEKpRAFp -> MEKp + RAFp d6 = 0.8 MEKppMEKPH -> MEKPH + MEKpp d7 = 0.6 MAPKMEKpp -> MAPK + MEKpp d8 = 0.4 MAPKpMAPKPH -> MAPKp + MAPKPH d9 = 0.6 MAPKpMEKpp -> MAPKp + MEKpp k10 = 0.1 MAPKppMAPKPH -> MAPKp + MAPKPH k1 = 0.1 RAFRAFK -> RAFK + RAFp k2 = 0.1 RAFpRAFPH -> RAF + RAFPH k3 = 0.1 MEKRAFp -> MEKp + RAFp k4 = 0.1 MEKpMEKPH -> MEK + MEKPH k5 = 0.1 MEKpRAFp -> MEKpp + RAFp k6 = 0.1 MEKppMEKPH -> MEKp + MEKPH k7 = 0.1 MAPKMEKpp -> MAPKp + MEKpp k8 = 0.1 MAPKpMAPKPH -> MAPK + MAPKPH k9 = 0.1 MAPKpMEKpp -> MAPKpp + MEKpp Variable IC ODE MAPK 0.3 MAPK'[t] == d7*MAPKMEKpp[t] + k8*MAPKpMAPKPH[t] - a7*MAPK[t]*MEKpp[t] MAPKMEKpp 0 MAPKMEKpp'[t] == -(d7*MAPKMEKpp[t]) - k7*MAPKMEKpp[t] + a7*MAPK[t]*MEKpp[t] MAPKp 0 MAPKp'[t] == k7*MAPKMEKpp[t] - a8*MAPKp[t]*MAPKPH[t] + d8*MAPKpMAPKPH[t] + d9*MAPKpMEKpp[t] + k10* MAPKppMAPKPH[t] - a9*MAPKp[t]*MEKpp[t] MAPKPH 0.3 MAPKPH'[t] == -(a8*MAPKp[t]*MAPKPH[t]) + d8*MAPKpMAPKPH[ t] + k8*MAPKpMAPKPH[t] - a10*MAPKPH[t]*MAPKpp[t] + d10*MAPKppMAPKPH[t] + k10*MAPKppMAPKPH[t] MAPKpMAPKPH 0 MAPKpMAPKPH'[t] == a8*MAPKp[t]*MAPKPH[t] - d8* MAPKpMAPKPH[t] - k8*MAPKpMAPKPH[t] MAPKpMEKpp 0 MAPKpMEKpp'[t] == -(d9*MAPKpMEKpp[t]) - k9*MAPKpMEKpp[t] + a9*MAPKp[t]*MEKpp[t] MAPKpp 0 MAPKpp'[t] == k9*MAPKpMEKpp[t] - a10*MAPKPH[t]*MAPKpp[t] + d10*MAPKppMAPKPH[t] MAPKppMAPKPH 0 MAPKppMAPKPH'[t] == a10*MAPKPH[t]*MAPKpp[t] - d10* MAPKppMAPKPH[t] - k10*MAPKppMAPKPH[t] MEK 0.2 MEK'[t] == k4*MEKpMEKPH[t] + d3*MEKRAFp[t] - a3*MEK[t]*RAFp[t] MEKp 0 MEKp'[t] == -(a4*MEKp[t]*MEKPH[t]) + d4*MEKpMEKPH[t] + k6*MEKppMEKPH[t] + d5*MEKpRAFp[t] + k3*MEKRAFp[ t] - a5*MEKp[t]*RAFp[t] MEKPH 0.2 MEKPH'[t] == -(a4*MEKp[t]*MEKPH[t]) + d4*MEKpMEKPH[t] + k4*MEKpMEKPH[t] - a6*MEKPH[t]*MEKpp[t] + d6* MEKppMEKPH[t] + k6*MEKppMEKPH[t] MEKpMEKPH 0 MEKpMEKPH'[t] == a4*MEKp[t]*MEKPH[t] - d4*MEKpMEKPH[t] - k4*MEKpMEKPH[t] MEKpp 0 MEKpp'[t] == d7*MAPKMEKpp[t] + k7*MAPKMEKpp[t] + d9*MAPKpMEKpp[t] + k9*MAPKpMEKpp[t] - a7*MAPK[t]* MEKpp[t] - a9*MAPKp[t]*MEKpp[t] - a6*MEKPH[t]*MEKpp[t] + d6*MEKppMEKPH[t] + k5*MEKpRAFp[t] MEKppMEKPH 0 MEKppMEKPH'[t] == a6*MEKPH[t]*MEKpp[t] - d6*MEKppMEKPH[ t] - k6*MEKppMEKPH[t] MEKpRAFp 0 MEKpRAFp'[t] == -(d5*MEKpRAFp[t]) - k5*MEKpRAFp[t] + a5*MEKp[t]*RAFp[t] MEKRAFp 0 MEKRAFp'[t] == -(d3*MEKRAFp[t]) - k3*MEKRAFp[t] + a3*MEK[t]*RAFp[t] RAF 0.4 RAF'[t] == -(a1*RAF[t]*RAFK[t]) + k2*RAFpRAFPH[t] + d1*RAFRAFK[t] RAFK 0.1 RAFK'[t] == -(a1*RAF[t]*RAFK[t]) + d1*RAFRAFK[t] + k1*RAFRAFK[t] RAFp 0 RAFp'[t] == d5*MEKpRAFp[t] + k5*MEKpRAFp[t] + d3*MEKRAFp[t] + k3*MEKRAFp[t] - a3*MEK[t]*RAFp[t] - a5*MEKp[t]*RAFp[t] - a2*RAFp[t]*RAFPH[t] + d2* RAFpRAFPH[t] + k1*RAFRAFK[t] RAFPH 0.3 RAFPH'[t] == -(a2*RAFp[t]*RAFPH[t]) + d2*RAFpRAFPH[t] + k2*RAFpRAFPH[t] RAFpRAFPH 0 RAFpRAFPH'[t] == a2*RAFp[t]*RAFPH[t] - d2*RAFpRAFPH[t] - k2*RAFpRAFPH[t] RAFRAFK 0 RAFRAFK'[t] == a1*RAF[t]*RAFK[t] - d1*RAFRAFK[t] - k1*RAFRAFK[t] Generated by Cellerator Version 1.4.3 (6-March-2004) using Mathematica 5.0 for Mac OS X (November 19, 2003), March 6, 2004 12:18:07, using (PowerMac, PowerPC,Mac OS X,MacOSX,Darwin) author=B.E.Shapiro This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2010 The BioModels.net Team. For more information see the terms of use . To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Dataset Information

Suppression of Transcriptional Drift Extends C. elegans Lifespan by Postponing the Onset of Mortality

Publications

Suppression of transcriptional drift extends C. elegans lifespan by postponing the onset of mortality.

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