Biology of Healthy Aging: Biological Hallmarks of Stress Resistance Related and Unrelated to Longevity in Humans
Abstract
:1. Introduction
2. Results
2.1. Stress Resistance
2.1.1. Databases and Overview of Stress Resistance
2.1.2. Stress Resistance: Cell-Cycle-Related Pathways
2.1.3. Stress Resistance: Signal Transduction–Gene Expression Pathways
2.1.4. Stress Resistance: Metabolic Pathways
2.1.5. Stress Resistance: Metabolism of Proteins, Metabolism of RNA, and Others
2.2. Longevity
2.3. Overlap for Stress Resistance and Longevity
3. Discussion
3.1. Similarity among Stress Resistance and Longevity Pathways
3.2. Differences among Stress Resistance and Longevity Pathways
3.3. Translation of the Results into Potential Therapeutic Targets or Interventions
3.3.1. Overlapped Pathway Categories between Stress Resistance and Longevity
3.3.2. Non-Overlapped Pathway Categories between Stress Resistance and Longevity
3.4. Advantages and Limitations of the Method
3.5. Nuclear Transport and Integrity Emphasized Stress Resistance and Aging but Not Longevity
4. Materials and Methods
4.1. Nomenclatures
4.2. Datasets
4.3. Gene Ontology
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Functional Enrichment Dimensions | Number of Hits |
---|---|
Biological Process (Gene Ontology) | 1359 GO-terms |
Molecular Function (Gene Ontology) | 162 GO-terms |
Cellular Component (Gene Ontology) | 163 GO-terms |
Reference publications (PubMed) | 10,000 publications |
Local network cluster (STRING) | 116 clusters |
KEGG Pathways | 125 pathways |
Reactome Pathways | 468 pathways |
GO (gene ontology) |
Pathways | No. of Pathways |
---|---|
Total Number of Pathways Identified | 172 |
Total Number of Pathway Categories Grouped * | 14 |
Breakdowns of 172 Pathway Categories | No. of pathways |
1 Cell Cycle | 40 |
2 DNA Repair | 37 |
3 Gene Expression (Transcription) | 19 |
4 Metabolism of Proteins | 17 |
5 Metabolism of RNA | 14 |
6 Signal Transduction | 14 |
7 Cellular Responses to Stimuli | 11 |
8 Immune System | 6 |
9 Metabolism | 4 |
10 Autophagy | 3 |
11 Chromatin Organization | 2 |
12 Developmental Biology | 2 |
13 Organelle Biogenesis | 2 |
14 DNA Replication | 1 |
Total | 172 |
Selected Pathways for Stress-Resistance Pathway Enrichment | |||||||||
---|---|---|---|---|---|---|---|---|---|
Reactome Pathway | Ratio of Protein in Pathway | Number of Protein in Pathway | Protein from Gene Set | p-Value | FDR | Hit Genes | General | Specific | More Specific |
Cell Cycle, Mitotic | 0.0478 | 530 | 86 | 1.11 × 10−16 | 4.44 × 10−15 | NUP107,SMC3,SMC4,SMC2,MYC,AKT1,NUP210,PRKCA,NUP93,PSME1,NUP98,NUP205,SEH1L,NUP85,RAD21,NUP88,PLK1,TUBA1B,TUBA1A,EMD,NDC1,SIRT2,TUBB2A,TUBB4B,PSMC6,PSMC3,NCAPD2,ANAPC7,LEMD2,KPNB1,ANAPC1,HSP90AB1,MCM7,FOXM1,TNPO1,RFC5,RFC3,HSP90AA1,RFC4,RFC1,RFC2,RANGAP1,SMC1A,MCM6,MCM2,HDAC1,RBBP4,H2AZ2,CDC27,RCC1,H4C1,SKP2,TMPO,TP53,WAPL,TOP2A,CETN2,SEC13,TUBB,SFI1,PCNA,LMNA,RAE1,H2BC3,RPA1,RPA2,RPA3,NUP188,CCND1,BANF1,PSMD11,PDS5A,NUP160,UBE2I,NUP155,LMNB1,NUP62,NUP133,NUP58,POLD3,POLD2,NUP43,BUB3,NUP35,RAN,NUP37 | Cell Cycle | Cell Cycle, Mitotic | Cell Cycle, Mitotic |
Mitotic Prophase | 0.0101 | 112 | 33 | 1.11 × 10−16 | 4.44 × 10−15 | NUP107,SMC4,SMC2,NUP210,PRKCA,NUP93,NUP98,NUP205,SEH1L,NUP85,NUP88,PLK1,EMD,NDC1,LEMD2,H2AZ2,H4C1,TMPO,SEC13,LMNA,RAE1,H2BC3,NUP188,BANF1,NUP160,NUP155,LMNB1,NUP62,NUP133,NUP58,NUP43,NUP35,NUP37 | Cell Cycle | Cell Cycle, Mitotic | Mitotic Prophase |
Mitotic Anaphase | 0.0212 | 235 | 48 | 1.11 × 10−16 | 4.44 × 10−15 | NUP107,SMC3,NUP93,PSME1,NUP98,NUP205,SEH1L,NUP85,RAD21,PLK1,TUBA1B,TUBA1A,EMD,NDC1,SIRT2,TUBB2A,TUBB4B,PSMC6,PSMC3,ANAPC7,LEMD2,KPNB1,ANAPC1,TNPO1,RANGAP1,SMC1A,CDC27,RCC1,TMPO,WAPL,SEC13,LMNA,NUP188,BANF1,PSMD11,PDS5A,NUP160,UBE2I,NUP155,LMNB1,NUP62,NUP133,NUP58,NUP43,BUB3,NUP35,RAN,NUP37 | Cell Cycle | Cell Cycle, Mitotic | Mitotic Anaphase |
Nuclear Envelope Breakdown | 0.0048 | 53 | 28 | 1.11 × 10−16 | 4.44 × 10−15 | NUP107,NUP210,PRKCA,NUP93,NUP98,NUP205,SEH1L,NUP85,NUP88,PLK1,EMD,NDC1,LEMD2,TMPO,SEC13,LMNA,RAE1,NUP188,BANF1,NUP160,NUP155,LMNB1,NUP62,NUP133,NUP58,NUP43,NUP35,NUP37 | Cell Cycle | Cell Cycle, Mitotic | Nuclear Envelope Breakdown |
M Phase | 0.0348 | 386 | 62 | 1.11 × 10−16 | 4.44 × 10−15 | NUP107,SMC3,SMC4,SMC2,NUP210,PRKCA,NUP93,PSME1,NUP98,NUP205,SEH1L,NUP85,RAD21,NUP88,PLK1,TUBA1B,TUBA1A,EMD,NDC1,SIRT2,TUBB2A,TUBB4B,PSMC6,PSMC3,NCAPD2,ANAPC7,LEMD2,KPNB1,ANAPC1,TNPO1,HSP90AA1,RANGAP1,SMC1A,H2AZ2,CDC27,RCC1,H4C1,TMPO,WAPL,CETN2,SEC13,TUBB,SFI1,LMNA,RAE1,H2BC3,NUP188,BANF1,PSMD11,PDS5A,NUP160,UBE2I,NUP155,LMNB1,NUP62,NUP133,NUP58,NUP43,BUB3,NUP35,RAN,NUP37 | Cell Cycle | Cell Cycle, Mitotic | M Phase |
Nuclear Pore Complex (NPC) Disassembly | 0.0032 | 36 | 20 | 1.11 × 10−16 | 4.44 × 10−15 | NUP107,NUP210,NUP93,NUP98,NUP205,SEH1L,NUP85,NUP88,NDC1,SEC13,RAE1,NUP188,NUP160,NUP155,NUP62,NUP133,NUP58,NUP43,NUP35,NUP37 | Cell Cycle | Cell Cycle, Mitotic | Nuclear Pore Complex (NPC) Disassembly |
Mitotic Metaphase and Anaphase | 0.0213 | 236 | 48 | 1.11 × 10−16 | 4.44 × 10−15 | NUP107,SMC3,NUP93,PSME1,NUP98,NUP205,SEH1L,NUP85,RAD21,PLK1,TUBA1B,TUBA1A,EMD,NDC1,SIRT2,TUBB2A,TUBB4B,PSMC6,PSMC3,ANAPC7,LEMD2,KPNB1,ANAPC1,TNPO1,RANGAP1,SMC1A,CDC27,RCC1,TMPO,WAPL,SEC13,LMNA,NUP188,BANF1,PSMD11,PDS5A,NUP160,UBE2I,NUP155,LMNB1,NUP62,NUP133,NUP58,NUP43,BUB3,NUP35,RAN,NUP37 | Cell Cycle | Cell Cycle, Mitotic | Mitotic Metaphase and Anaphase |
Postmitotic Nuclear Pore Complex (NPC) Reformation | 0.0024 | 27 | 23 | 1.11 × 10−16 | 4.44 × 10−15 | NUP107,NUP93,NUP98,NUP205,SEH1L,NUP85,NDC1,KPNB1,TNPO1,RANGAP1,RCC1,SEC13,NUP188,NUP160,UBE2I,NUP155,NUP62,NUP133,NUP58,NUP43,NUP35,RAN,NUP37 | Cell Cycle | Cell Cycle, Mitotic | Postmitotic Nuclear Pore Complex (NPC) Reformation |
Nuclear Envelope (NE) Reassembly | 0.0068 | 76 | 34 | 1.11 × 10−16 | 4.44 × 10−15 | NUP107,NUP93,NUP98,NUP205,SEH1L,NUP85,TUBA1B,TUBA1A,EMD,NDC1,SIRT2,TUBB2A,TUBB4B,LEMD2,KPNB1,TNPO1,RANGAP1,RCC1,TMPO,SEC13,LMNA,NUP188,BANF1,NUP160,UBE2I,NUP155,LMNB1,NUP62,NUP133,NUP58,NUP43,NUP35,RAN,NUP37 | Cell Cycle | Cell Cycle, Mitotic | Nuclear Envelope (NE) Reassembly |
S Phase | 0.0147 | 163 | 31 | 2.68 × 10−12 | 6.43 × 10−11 | SMC3,MYC,AKT1,PSME1,RAD21,PSMC6,PSMC3,ANAPC7,ANAPC1,MCM7,RFC5,RFC3,RFC4,RFC1,RFC2,SMC1A,MCM6,MCM2,RBBP4,CDC27,SKP2,WAPL,PCNA,RPA1,RPA2,RPA3,CCND1,PSMD11,PDS5A,POLD3,POLD2 | Cell Cycle | Cell Cycle, Mitotic | S Phase |
DNA Strand Elongation | 0.0029 | 32 | 14 | 1.08 × 10−10 | 2.38 × 10−9 | MCM7,RFC5,RFC3,RFC4,RFC1,RFC2,MCM6,MCM2,PCNA,RPA1,RPA2,RPA3,POLD3,POLD2 | Cell Cycle | Cell Cycle, Mitotic | DNA Strand Elongation |
Lagging Strand Synthesis | 0.0018 | 20 | 11 | 1.05 × 10−9 | 1.99 × 10−8 | RFC5,RFC3,RFC4,RFC1,RFC2,PCNA,RPA1,RPA2,RPA3,POLD3,POLD2 | Cell Cycle | Cell Cycle, Mitotic | Lagging Strand Synthesis |
Synthesis of DNA | 0.0109 | 121 | 22 | 9.19 × 10−9 | 1.38 × 10−7 | PSME1,PSMC6,PSMC3,ANAPC7,ANAPC1,MCM7,RFC5,RFC3,RFC4,RFC1,RFC2,MCM6,MCM2,CDC27,SKP2,PCNA,RPA1,RPA2,RPA3,PSMD11,POLD3,POLD2 | Cell Cycle | Cell Cycle, Mitotic | Synthesis of DNA |
Mitotic Prometaphase | 0.0169 | 188 | 26 | 9.57 × 10−8 | 1.15 × 10−6 | NUP107,SMC3,SMC4,SMC2,NUP98,SEH1L,NUP85,RAD21,PLK1,TUBA1A,TUBB4B,NCAPD2,HSP90AA1,RANGAP1,SMC1A,WAPL,CETN2,SEC13,TUBB,SFI1,PDS5A,NUP160,NUP133,NUP43,BUB3,NUP37 | Cell Cycle | Cell Cycle, Mitotic | Mitotic Prometaphase |
Polymerase Switching | 0.0013 | 14 | 8 | 1.51 × 10−7 | 1.81 × 10−6 | RFC5,RFC3,RFC4,RFC1,RFC2,PCNA,POLD3,POLD2 | Cell Cycle | Cell Cycle, Mitotic | Polymerase switching |
Leading Strand Synthesis | 0.0013 | 14 | 8 | 1.51 × 10−7 | 1.81 × 10−6 | RFC5,RFC3,RFC4,RFC1,RFC2,PCNA,POLD3,POLD2 | Cell Cycle | Cell Cycle, Mitotic | Leading Strand Synthesis |
Separation of Sister Chromatids | 0.0155 | 172 | 24 | 2.55 × 10−7 | 2.81 × 10−6 | NUP107,SMC3,PSME1,NUP98,SEH1L,NUP85,RAD21,PLK1,PSMC6,PSMC3,ANAPC7,ANAPC1,RANGAP1,SMC1A,CDC27,WAPL,SEC13,PSMD11,PDS5A,NUP160,NUP133,NUP43,BUB3,NUP37 | Cell Cycle | Cell Cycle, Mitotic | Separation of Sister Chromatids |
Initiation of Nuclear Envelope (NE) Reformation | 0.0017 | 19 | 8 | 1.46 × 10−6 | 1.39 × 10−5 | EMD,SIRT2,LEMD2,KPNB1,TMPO,LMNA,BANF1,LMNB1 | Cell Cycle | Cell Cycle, Mitotic | Initiation of Nuclear Envelope (NE) Reformation |
Resolution of Sister Chromatid Cohesion | 0.0096 | 107 | 17 | 2.70 × 10−6 | 2.43 × 10−5 | NUP107,SMC3,NUP98,SEH1L,NUP85,RAD21,PLK1,RANGAP1,SMC1A,WAPL,SEC13,PDS5A,NUP160,NUP133,NUP43,BUB3,NUP37 | Cell Cycle | Cell Cycle, Mitotic | Resolution of Sister Chromatid Cohesion |
Mitotic Telophase/Cytokinesis | 0.0012 | 13 | 6 | 1.83 × 10−5 | 1.46 × 10−4 | SMC3,RAD21,PLK1,SMC1A,WAPL,PDS5A | Cell Cycle | Cell Cycle, Mitotic | Mitotic Telophase/Cytokinesis |
Removal of the Flap Intermediate | 0.0013 | 14 | 6 | 2.75 × 10−5 | 1.93 × 10−4 | PCNA,RPA1,RPA2,RPA3,POLD3,POLD2 | Cell Cycle | Cell Cycle, Mitotic | Removal of the Flap Intermediate |
G1/S Transition | 0.0118 | 131 | 17 | 3.50 × 10−5 | 2.45 × 10−4 | MYC,AKT1,PSME1,PSMC6,PSMC3,MCM7,MCM6,MCM2,HDAC1,RBBP4,SKP2,PCNA,RPA1,RPA2,RPA3,CCND1,PSMD11 | Cell Cycle | Cell Cycle, Mitotic | G1/S Transition |
Processive Synthesis on the Lagging Strand | 0.0014 | 15 | 6 | 4.03 × 10−5 | 2.82 × 10−4 | PCNA,RPA1,RPA2,RPA3,POLD3,POLD2 | Cell Cycle | Cell Cycle, Mitotic | Processive Synthesis on the Lagging Strand |
Depolymerization of the Nuclear Lamina | 0.0014 | 15 | 6 | 4.03 × 10−5 | 2.82 × 10−4 | PRKCA,EMD,LEMD2,TMPO,LMNA,LMNB1 | Cell Cycle | Cell Cycle, Mitotic | Depolymerization of the Nuclear Lamina |
Mitotic G1 phase and G1/S transition | 0.0134 | 149 | 18 | 5.17 × 10−5 | 3.29 × 10−4 | MYC,AKT1,PSME1,PSMC6,PSMC3,MCM7,MCM6,MCM2,HDAC1,RBBP4,SKP2,TOP2A,PCNA,RPA1,RPA2,RPA3,CCND1,PSMD11 | Cell Cycle | Cell Cycle, Mitotic | Mitotic G1 Phase and G1/S Transition |
Cohesin Loading Onto Chromatin | 0.0009 | 10 | 5 | 6.34 × 10−5 | 3.81 × 10−4 | SMC3,RAD21,SMC1A,WAPL,PDS5A | Cell Cycle | Cell Cycle, Mitotic | Cohesin Loading onto Chromatin |
Establishment of Sister Chromatid Cohesion | 0.001 | 11 | 5 | 9.88 × 10−5 | 5.93 × 10−4 | SMC3,RAD21,SMC1A,WAPL,PDS5A | Cell Cycle | Cell Cycle, Mitotic | Establishment of Sister Chromatid Cohesion |
Selected Pathways for Longevity Pathway Enrichment | |||||||||
---|---|---|---|---|---|---|---|---|---|
Reactome Pathway | Ratio of Protein in Pathway | Number of Proteins in Pathway | Protein from Gene Set | p-Value | FDR | Hit Genes | General | Specific | More Specific |
MTOR signaling | 0.0037 | 41 | 19 | 1.11 × 10−16 | 5.34 × 10−14 | AKT1,RRAGA,RRAGC,RRAGB,RRAGD,RPTOR,LAMTOR2,LAMTOR3,RPS6,TSC2,TSC1,EIF4EBP1,RHEB,MLST8,AKT1S1,EIF4E,EIF4B,MTOR,RPS6KB1 | Signal transduction | MTOR signaling | |
mTORC1-mediated signaling | 0.0022 | 24 | 16 | 1.11 × 10−16 | 5.34 × 10−14 | RRAGA,RRAGC,RRAGB,RRAGD,RPTOR,LAMTOR2,LAMTOR3,RPS6,EIF4EBP1,RHEB,MLST8,AKT1S1,EIF4E,EIF4B,MTOR,RPS6KB1 | Signal transduction | MTOR signaling | mTORC1-mediated signaling |
Intracellular signaling by second messengers | 0.0294 | 326 | 34 | 1.29 × 10−14 | 4.12 × 10−12 | AKT1,PRKCA,RRAGA,RRAGC,RRAGB,RRAGD,TP53,MAPKAP1,TGFA,INSR,CDKN1A,RPTOR,PPARG,EGFR,RICTOR,CAMK4,LAMTOR2,LAMTOR3,IRS2,TSC2,FOXO4,FOXO3,FOXO1,KL,ESR1,NBEA,RHEB,FGFR1,PRR5,MLST8,PIK3CA,AKT1S1,INS,MTOR | Signal transduction | Intracellular signaling by second messengers | |
PIP3 activates AKT signaling | 0.0258 | 286 | 31 | 7.83 × 10−14 | 1.88 × 10−11 | AKT1,RRAGA,RRAGC,RRAGB,RRAGD,TP53,MAPKAP1,TGFA,INSR,CDKN1A,RPTOR,PPARG,EGFR,RICTOR,LAMTOR2,LAMTOR3,IRS2,TSC2,FOXO4,FOXO3,FOXO1,KL,ESR1,RHEB,FGFR1,PRR5,MLST8,PIK3CA,AKT1S1,INS,MTOR | Signal transduction | Intracellular signaling by second messengers | PIP3 activates AKT signaling |
Generic transcription pathway | 0.1113 | 1235 | 66 | 2.29 × 10−13 | 4.40 × 10−11 | SERPINE1,AKT1,RUNX3,RRAGA,RRAGC,RRAGB,RRAGD,TP53,MAPKAP1,TGFA,GATA4,APOE,ATRIP,PPARGC1A,ATM,CDKN1A,MSTN,RPTOR,SREBF1,SIRT1,SIRT3,RAD51D,RARB,PPARG,SGK1,EGFR,WRN,RICTOR,WWOX,CDKN2B,GSR,MLH1,VEGFA,CAMK4,FAS,LAMTOR2,LAMTOR3,NR3C1,YY1,KCTD1,TSC2,TSC1,TBL1XR1,CSF1R,FOXO4,FOXO3,FOXO1,PLXNA4,TGFB1,ESRRG,ESR1,NFKB1,IL6,CDK6,RHEB,PRR5,EXO1,MLST8,YWHAG,H2AFX,IFNG,INS,TXNRD1,SOD2,MTOR,ERCC2 | Gene expression (transcription) | RNA polymerase II transcription | Generic transcription pathway |
Energy-dependent regulation of mTOR by LKB1-AMPK | 0.0026 | 29 | 12 | 1.95 × 10−12 | 3.12 × 10−10 | RRAGA,RRAGC,RRAGB,RRAGD,RPTOR,LAMTOR2,LAMTOR3,TSC2,TSC1,RHEB,MLST8,MTOR | Signal transduction | MTOR signaling | Energy-dependent regulation of mTOR by LKB1-AMPK |
RNA polymerase II transcription | 0.1229 | 1364 | 67 | 6.72 × 10−12 | 9.20 × 10−10 | SERPINE1,AKT1,RUNX3,RRAGA,RRAGC,RRAGB,RRAGD,TP53,MAPKAP1,TGFA,GATA4,APOE,ATRIP,PPARGC1A,ATM,CDKN1A,MSTN,RPTOR,SREBF1,SIRT1,SIRT3,RAD51D,RARB,PPARG,SGK1,EGFR,WRN,RICTOR,WWOX,CDKN2B,GSR,MLH1,VEGFA,CAMK4,FAS,LAMTOR2,LAMTOR3,NR3C1,YY1,KCTD1,TSC2,TSC1,TBL1XR1,CSF1R,FOXO4,FOXO3,FOXO1,PLXNA4,TGFB1,ESRRG,ESR1,NFKB1,IL6,CDK6,RHEB,PRR5,EXO1,MLST8,YWHAG,H2AFX,IFNG,POLDIP3,INS,TXNRD1,SOD2,MTOR,ERCC2 | Gene expression (transcription) | RNA polymerase II transcription | |
TP53 regulates metabolic genes | 0.008 | 89 | 17 | 9.43 × 10−12 | 1.13 × 10−9 | AKT1,RRAGA,RRAGC,RRAGB,RRAGD,TP53,RPTOR,GSR,LAMTOR2,LAMTOR3,TSC2,TSC1,RHEB,MLST8,YWHAG,TXNRD1,MTOR | Gene expression (transcription) | RNA polymerase II transcription | Generic transcription pathway |
FOXO-mediated transcription | 0.006 | 67 | 15 | 1.84 × 10−11 | 1.95 × 10−9 | AKT1,PPARGC1A,CDKN1A,MSTN,SREBF1,SIRT1,SIRT3,NR3C1,FOXO4,FOXO3,FOXO1,PLXNA4,YWHAG,INS,SOD2 | Gene expression (transcription) | RNA polymerase II transcription | Generic transcription pathway |
Transcriptional regulation by TP53 | 0.0332 | 368 | 30 | 2.09 × 10−10 | 1.82 × 10−8 | AKT1,RRAGA,RRAGC,RRAGB,RRAGD,TP53,MAPKAP1,ATRIP,ATM,CDKN1A,RPTOR,RAD51D,SGK1,WRN,RICTOR,GSR,MLH1,FAS,LAMTOR2,LAMTOR3,TSC2,TSC1,RHEB,PRR5,EXO1,MLST8,YWHAG,TXNRD1,MTOR,ERCC2 | Gene expression (transcription) | RNA polymerase II transcription | Generic transcription pathway |
FOXO-mediated transcription of oxidative stress and metabolic and neuronal genes | 0.0028 | 31 | 10 | 1.49 × 10−9 | 1.19 × 10−7 | PPARGC1A,SREBF1,SIRT3,NR3C1,FOXO4,FOXO3,FOXO1,PLXNA4,INS,SOD2 | Gene expression (transcription) | RNA polymerase II transcription | Generic transcription pathway |
Regulation of PTEN gene transcription | 0.0055 | 61 | 12 | 8.21 × 10−9 | 5.58 × 10−7 | RRAGA,RRAGC,RRAGB,RRAGD,TP53,RPTOR,PPARG,LAMTOR2,LAMTOR3,RHEB,MLST8,MTOR | Signal transduction | Intracellular signaling by second messengers | PIP3 activates AKT signaling |
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors | 0.0032 | 36 | 9 | 8.53 × 10−8 | 4.78 × 10−6 | TGFA,APOE,CDKN1A,EGFR,WWOX,VEGFA,YY1,KCTD1,ESR1 | Gene expression (transcription) | RNA polymerase II transcription | Generic transcription pathway |
Regulation of TP53 degradation | 0.0032 | 36 | 9 | 8.53 × 10−8 | 4.78 × 10−6 | AKT1,TP53,MAPKAP1,ATM,SGK1,RICTOR,PRR5,MLST8,MTOR | Gene expression (transcription) | RNA polymerase II transcription | Generic transcription pathway |
Regulation of TP53 expression and degradation | 0.0033 | 37 | 9 | 1.07 × 10−7 | 5.69 × 10−6 | AKT1,TP53,MAPKAP1,ATM,SGK1,RICTOR,PRR5,MLST8,MTOR | Gene expression (transcription) | RNA polymerase II transcription | Generic transcription pathway |
VEGFA-VEGFR2 pathway | 0.0086 | 95 | 12 | 9.06 × 10−7 | 3.35 × 10−5 | AKT1,PRKCA,MAPKAP1,HRAS,RHOA,RICTOR,VEGFA,PRR5,ITGB3,MLST8,PIK3CA,MTOR | Signal transduction | Signaling by receptor tyrosine kinases | Signaling by VEGF |
Signaling by VEGF | 0.0094 | 104 | 12 | 2.28 × 10−6 | 7.99 × 10−5 | AKT1,PRKCA,MAPKAP1,HRAS,RHOA,RICTOR,VEGFA,PRR5,ITGB3,MLST8,PIK3CA,MTOR | Signal transduction | Signaling by receptor tyrosine kinases | Signaling by VEGF |
Regulation of FOXO transcriptional activity by acetylation | 0.0009 | 10 | 5 | 2.52 × 10−6 | 8.33 × 10−5 | SIRT1,SIRT3,FOXO4,FOXO3,FOXO1 | Gene expression (transcription) | RNA polymerase II transcription | Generic transcription pathway |
Regulation of localization of FOXO transcription factors | 0.0011 | 12 | 5 | 6.07 × 10−6 | 1.76 × 10−4 | AKT1,FOXO4,FOXO3,FOXO1,YWHAG | Gene expression (transcription) | RNA polymerase II transcription | Generic transcription pathway |
Signaling by receptor tyrosine kinases | 0.0458 | 508 | 27 | 7.81 × 10−6 | 2.19 × 10−4 | AKT1,PRKCA,MAPKAP1,TGFA,HIF1A,APOE,LYN,INSR,IGF2,HRAS,RHOA,SGK1,EGFR,RICTOR,WWOX,VEGFA,IRS2,IGF1R,KL,ESR1,FGFR1,PRR5,ITGB3,MLST8,PIK3CA,INS,MTOR | Signal transduction | Signaling by receptor tyrosine kinases | |
TFAP2 (AP-2) family regulates transcription of growth factors and their receptors | 0.0012 | 13 | 5 | 8.91 × 10−6 | 2.22 × 10−4 | TGFA,EGFR,VEGFA,YY1,ESR1 | Gene expression (transcription) | RNA polymerase II transcription | Generic transcription pathway |
RUNX3 regulates CDKN1A transcription | 0.0006 | 7 | 4 | 1.58 × 10−5 | 3.63 × 10−4 | RUNX3,TP53,CDKN1A,TGFB1 | Gene expression (transcription) | RNA polymerase II transcription | Generic transcription pathway |
VEGFR2 mediated vascular permeability | 0.0024 | 27 | 6 | 2.45 × 10−5 | 5.39 × 10−4 | AKT1,MAPKAP1,RICTOR,PRR5,MLST8,MTOR | Signal transduction | Signaling by receptor tyrosine kinases | Signaling by VEGF |
PTEN regulation | 0.0142 | 158 | 13 | 3.09 × 10−5 | 6.69 × 10−4 | AKT1,RRAGA,RRAGC,RRAGB,RRAGD,TP53,RPTOR,PPARG,LAMTOR2,LAMTOR3,RHEB,MLST8,MTOR | Signal transduction | Intracellular signaling by second messengers | PIP3 activates AKT signaling |
FOXO-mediated transcription of cell cycle genes | 0.0015 | 17 | 5 | 3.19 × 10−5 | 6.69 × 10−4 | CDKN1A,MSTN,FOXO4,FOXO3,FOXO1 | Gene expression (transcription) | RNA polymerase II transcription | Generic transcription pathway |
Signaling by nuclear receptors | 0.0245 | 272 | 17 | 6.09 × 10−5 | 1.22 × 10−3 | AKT1,CETP,TGFA,APOE,HRAS,SREBF1,RARB,DLD,EGFR,IGF1R,YY1,TBL1XR1,FOXO3,ESR1,H2AFX,PIK3CA,APOC1 | Signal transduction | Signaling by nuclear receptors | |
AKT phosphorylates targets in the nucleus | 0.0009 | 10 | 4 | 6.26 × 10−5 | 1.22 × 10−3 | AKT1,FOXO4,FOXO3,FOXO1 | Signal transduction | Intracellular signaling by second messengers | PIP3 activates AKT signaling |
PI5P, PP2A, and IER3 regulate PI3K/AKT signaling | 0.0096 | 106 | 10 | 8.53 × 10−5 | 1.62 × 10−3 | AKT1,TGFA,INSR,EGFR,IRS2,KL,ESR1,FGFR1,PIK3CA,INS | Signal transduction | Intracellular signaling by second messengers | PIP3 activates AKT signaling |
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Badial, K.; Lacayo, P.; Murakami, S. Biology of Healthy Aging: Biological Hallmarks of Stress Resistance Related and Unrelated to Longevity in Humans. Int. J. Mol. Sci. 2024, 25, 10493. https://doi.org/10.3390/ijms251910493
Badial K, Lacayo P, Murakami S. Biology of Healthy Aging: Biological Hallmarks of Stress Resistance Related and Unrelated to Longevity in Humans. International Journal of Molecular Sciences. 2024; 25(19):10493. https://doi.org/10.3390/ijms251910493
Chicago/Turabian StyleBadial, Komalpreet, Patricia Lacayo, and Shin Murakami. 2024. "Biology of Healthy Aging: Biological Hallmarks of Stress Resistance Related and Unrelated to Longevity in Humans" International Journal of Molecular Sciences 25, no. 19: 10493. https://doi.org/10.3390/ijms251910493
APA StyleBadial, K., Lacayo, P., & Murakami, S. (2024). Biology of Healthy Aging: Biological Hallmarks of Stress Resistance Related and Unrelated to Longevity in Humans. International Journal of Molecular Sciences, 25(19), 10493. https://doi.org/10.3390/ijms251910493