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Reactions

reaction_1

reaction_1

Akt > Akt_pS473

reaction_10

reaction_10

Mitophagy > Nil

reaction_11

reaction_11

FoxO3a > FoxO3a_pS253

reaction_12

reaction_12

FoxO3a_pS253 > FoxO3a

reaction_13

reaction_13

FoxO3a_pS253 > Nil

reaction_14

reaction_14

∅ > FoxO3a

reaction_15

reaction_15

∅ > CDKN1A

reaction_16

reaction_16

CDKN1A > Nil

reaction_17

reaction_17

∅ > CDKN1B

reaction_18

reaction_18

CDKN1B > Nil

reaction_19

reaction_19

∅ > DNA_damage

reaction_2

reaction_2

Akt_pS473 > Akt

reaction_20

reaction_20

∅ > DNA_damage

reaction_21

reaction_21

DNA_damage > Nil

reaction_22

reaction_22

∅ > ROS

reaction_23

reaction_23

∅ > ROS

reaction_24

reaction_24

ROS > Nil

reaction_25

reaction_25

JNK > JNK_pT183

reaction_26

reaction_26

JNK_pT183 > JNK

reaction_27

reaction_27

∅ > SA_beta_gal

reaction_28

reaction_28

∅ > SA_beta_gal

reaction_29

reaction_29

SA_beta_gal > ∅

reaction_3

reaction_3

AMPK > AMPK_pT172

reaction_30

reaction_30

Mito_mass_turnover > Mito_mass_new

reaction_31

reaction_31

Mito_mass_turnover > Mito_mass_new

reaction_32

reaction_32

Mito_mass_new > Mito_mass_turnover

reaction_33

reaction_33

Mito_mass_old > Mito_mass_turnover

reaction_34

reaction_34

Mito_mass_new > Mito_mass_old

reaction_35

reaction_35

∅ > Mito_membr_pot_new

reaction_36

reaction_36

∅ > Mito_membr_pot_old

reaction_37

reaction_37

Mito_membr_pot_new > Nil

reaction_38

reaction_38

Mito_membr_pot_old > Nil

reaction_39

reaction_39

∅ > IKKbeta

reaction_4

reaction_4

AMPK_pT172 > AMPK

reaction_40

reaction_40

IKKbeta > Nil

reaction_41

reaction_41

mTORC1 > mTORC1_pS2448

reaction_5

reaction_5

AMPK_pT172 > AMPK

reaction_6

reaction_6

mTORC1 > mTORC1_pS2448

reaction_7

reaction_7

mTORC1 > mTORC1_pS2448

reaction_8

reaction_8

mTORC1_pS2448 > mTORC1

reaction_9

reaction_9

∅ > Mitophagy

Parameters

Global parameters

Fixed species

Initial values

Functions and Rules

Assignment rules

Akt_pS473_obs = scale_Akt_pS473_obs * Akt_pS473

Irradiation = piecewise(0.0, lt(time, -1.0), piecewise(0.0, lt(time, 0.0), piecewise(1.0, lt(time, 0.003472), 0.0)))

Amino_Acids = piecewise(1.0, lt(time, -1.0), piecewise(1.0, lt(time, 0.0), 1.0))

Insulin = piecewise(1.0, lt(time, -1.0), piecewise(1.0, lt(time, 0.0), 1.0))

DNA_damage_gammaH2AX_obs = scale_DNA_damage_gammaH2AX_obs * DNA_damage

mTOR_pS2448_obs = scale_mTOR_pS2448_obs * mTORC1_pS2448

FoxO3a_pS253_obs = scale_FoxO3a_pS253_obs * FoxO3a_pS253

AMPK_pT172_obs = scale_AMPK_pT172_obs * AMPK_pT172

Mito_Mass_obs = scale_Mito_Mass_obs * (Mito_mass_new + Mito_mass_old)

CDKN1A_obs = scale_CDKN1A_obs * CDKN1A

CDKN1B_obs = scale_CDKN1B_obs * CDKN1B

Mito_Membr_Pot_obs = scale_Mito_Membr_Pot_obs * (Mito_membr_pot_new + Mito_membr_pot_old)

Mitophagy_obs = scale_Mitophagy_obs * Mitophagy

FoxO3a_total_obs = scale_FoxO3a_total_obs * (FoxO3a + FoxO3a_pS253)

ROS_obs = scale_ROS_obs * ROS

JNK_pT183_obs = scale_JNK_pT183_obs * JNK_pT183

SA_beta_gal_obs = scale_SA_beta_gal_obs * SA_beta_gal

Function definitions

function_2(v) = v

function_4_reaction_1_1(Akt, Akt_S473_phos_by_insulin, Insulin) = Akt_S473_phos_by_insulin * Akt * Insulin

function_4_reaction_2_1(Akt_pS473, Akt_pS473_dephos_by_mTORC1_pS2448, mTORC1_pS2448) = Akt_pS473_dephos_by_mTORC1_pS2448 * Akt_pS473 * mTORC1_pS2448

function_4_reaction_4_1(AMPK_pT172, AMPK_pT172_dephos_by_Mito_membr_pot_new, Mito_membr_pot_new) = AMPK_pT172_dephos_by_Mito_membr_pot_new * AMPK_pT172 * Mito_membr_pot_new

function_4_reaction_6_1(Amino_Acids, mTORC1, mTORC1_S2448_phos_by_AA) = mTORC1_S2448_phos_by_AA * mTORC1 * Amino_Acids

function_4_reaction_8_1(AMPK_pT172, mTORC1_pS2448, mTORC1_pS2448_dephos_by_AMPK_pT172) = mTORC1_pS2448_dephos_by_AMPK_pT172 * mTORC1_pS2448 * AMPK_pT172

function_4_reaction_10_1(Mitophagy, mTORC1_pS2448, mitophagy_inactiv_by_mTORC1_pS2448) = mitophagy_inactiv_by_mTORC1_pS2448 * Mitophagy * mTORC1_pS2448

function_4_reaction_11_1(Akt_pS473, FoxO3a, FoxO3a_phos_by_Akt_pS473) = FoxO3a_phos_by_Akt_pS473 * FoxO3a * Akt_pS473

function_4_reaction_15_1(CDKN1A_transcr_by_FoxO3a_n_DNA_damage, DNA_damage, FoxO3a) = CDKN1A_transcr_by_FoxO3a_n_DNA_damage * DNA_damage * FoxO3a

function_4_reaction_17_1(CDKN1B_transcr_by_FoxO3a_n_DNA_damage, DNA_damage, FoxO3a) = CDKN1B_transcr_by_FoxO3a_n_DNA_damage * DNA_damage * FoxO3a

function_4_reaction_19_1(DNA_damaged_by_irradiation, Irradiation) = DNA_damaged_by_irradiation * Irradiation

function_4_reaction_20_1(DNA_damaged_by_ROS, ROS) = DNA_damaged_by_ROS * ROS

function_4_reaction_22_1(Mito_membr_pot_new, ROS_prod_by_Mito_membr_pot_new) = ROS_prod_by_Mito_membr_pot_new * Mito_membr_pot_new

function_4_reaction_25_1(JNK, JNK_activ_by_ROS, ROS) = JNK_activ_by_ROS * JNK * ROS

function_4_reaction_28_1(Mitophagy, sen_ass_beta_gal_inc_by_Mitophagy) = sen_ass_beta_gal_inc_by_Mitophagy * Mitophagy

function_4_reaction_30_1(Mito_mass_turnover, mTORC1_pS2448, mito_biogenesis_by_mTORC1_pS2448) = mito_biogenesis_by_mTORC1_pS2448 * Mito_mass_turnover * mTORC1_pS2448

function_4_reaction_32_1(Mito_mass_new, Mitophagy, mitophagy_new) = mitophagy_new * Mito_mass_new * Mitophagy

function_4_reaction_33_1(Mito_mass_old, Mitophagy, mitophagy_old) = mitophagy_old * Mito_mass_old * Mitophagy

function_4_reaction_41_1(Amino_Acids, IKKbeta, mTORC1, mTORC1_S2448_phos_by_AA_n_IKKbeta) = mTORC1_S2448_phos_by_AA_n_IKKbeta * mTORC1 * Amino_Acids * IKKbeta

function_4_reaction_39_1(IKKbeta_activ_by_ROS, ROS) = IKKbeta_activ_by_ROS * ROS

function_4_reaction_36_1(Mito_mass_old, mito_membr_pot_old_inc) = mito_membr_pot_old_inc * Mito_mass_old

function_4_reaction_35_1(Mito_mass_new, mito_membr_pot_new_inc) = mito_membr_pot_new_inc * Mito_mass_new

function_4_reaction_34_1(CDKN1A, Mito_mass_new, mito_dysfunction) = mito_dysfunction * Mito_mass_new * CDKN1A

function_4_reaction_31_1(Mito_mass_turnover, mTORC1_pS2448, mito_biogenesis_by_AMPK_pT172) = mito_biogenesis_by_AMPK_pT172 * Mito_mass_turnover * mTORC1_pS2448

function_4_reaction_27_1(ROS, sen_ass_beta_gal_inc_by_ROS) = sen_ass_beta_gal_inc_by_ROS * ROS

function_4_reaction_23_1(Mito_membr_pot_old, ROS_prod_by_Mito_membr_pot_old) = ROS_prod_by_Mito_membr_pot_old * Mito_membr_pot_old

function_4_reaction_18_1(Akt_pS473, CDKN1B, CDKN1B_inactiv_by_Akt_pS473) = CDKN1B_inactiv_by_Akt_pS473 * CDKN1B * Akt_pS473

function_4_reaction_16_1(Akt_pS473, CDKN1A, CDKN1A_inactiv_by_Akt_pS473) = CDKN1A_inactiv_by_Akt_pS473 * CDKN1A * Akt_pS473

function_4_reaction_12_1(FoxO3a_pS253, FoxO3a_phos_by_JNK_pT183, JNK_pT183) = FoxO3a_phos_by_JNK_pT183 * FoxO3a_pS253 * JNK_pT183

function_4_reaction_9_1(AMPK_pT172, FoxO3a, mitophagy_activ_by_FoxO3a_n_AMPK_pT172) = mitophagy_activ_by_FoxO3a_n_AMPK_pT172 * FoxO3a * AMPK_pT172

function_4_reaction_7_1(Akt_pS473, Amino_Acids, mTORC1, mTORC1_S2448_phos_by_AA_n_Akt_pS473) = mTORC1_S2448_phos_by_AA_n_Akt_pS473 * mTORC1 * Amino_Acids * Akt_pS473

function_4_reaction_5_1(AMPK_pT172, AMPK_pT172_dephos_by_Mito_membr_pot_old, Mito_membr_pot_old) = AMPK_pT172_dephos_by_Mito_membr_pot_old * AMPK_pT172 * Mito_membr_pot_old

Events

Constraints

Note that constraints are not enforced in simulations. It remains the responsibility of the user to verify that simulation results satisfy these constraints.


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Reactions:

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Dynamic modelling of pathways to cellular senescence reveals strategies for targeted interventions.

  • Piero Dalle Pezze
  • Glyn Nelson
  • Elsje G Otten
  • Viktor I Korolchuk
  • Thomas B L Kirkwood
  • Thomas von Zglinicki
  • Daryl P Shanley
PLoS Comput. Biol. 2014; 10 (8):
Abstract
Cellular senescence, a state of irreversible cell cycle arrest, is thought to help protect an organism from cancer, yet also contributes to ageing. The changes which occur in senescence are controlled by networks of multiple signalling and feedback pathways at the cellular level, and the interplay between these is difficult to predict and understand. To unravel the intrinsic challenges of understanding such a highly networked system, we have taken a systems biology approach to cellular senescence. We report a detailed analysis of senescence signalling via DNA damage, insulin-TOR, FoxO3a transcription factors, oxidative stress response, mitochondrial regulation and mitophagy. We show in silico and in vitro that inhibition of reactive oxygen species can prevent loss of mitochondrial membrane potential, whilst inhibition of mTOR shows a partial rescue of mitochondrial mass changes during establishment of senescence. Dual inhibition of ROS and mTOR in vitro confirmed computational model predictions that it was possible to further reduce senescence-induced mitochondrial dysfunction and DNA double-strand breaks. However, these interventions were unable to abrogate the senescence-induced mitochondrial dysfunction completely, and we identified decreased mitochondrial fission as the potential driving force for increased mitochondrial mass via prevention of mitophagy. Dynamic sensitivity analysis of the model showed the network stabilised at a new late state of cellular senescence. This was characterised by poor network sensitivity, high signalling noise, low cellular energy, high inflammation and permanent cell cycle arrest suggesting an unsatisfactory outcome for treatments aiming to delay or reverse cellular senescence at late time points. Combinatorial targeted interventions are therefore possible for intervening in the cellular pathway to senescence, but in the cases identified here, are only capable of delaying senescence onset.
The SBML for this model was obtained from the BioModels database (BioModels ID: BIOMD0000000582) Biomodels notes: Figure 1 of the reference publication has been reproduced here. The model was simulated using Copasi and the plots were generated using gnuplot. JWS Online curation: This model was curated by reproducing the figures as described in the BioModels Notes. No additional changes were made.