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protein_description: 'RecName: Full=Transcription factor atf-4 homolog {ECO:0000303|PubMed:35181679};
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organism_full: Caenorhabditis elegans.
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

• UniProt Accession: Q22156
• Protein Description: RecName: Full=Transcription factor atf-4 homolog {ECO:0000303|PubMed:35181679}; AltName: Full=cAMP-dependent transcription factor family member 4 {ECO:0000312|WormBase:T04C10.4};
• Gene Information: Name=atf-4 {ECO:0000312|WormBase:T04C10.4}; Synonyms=atf-5 {ECO:0000312|WormBase:T04C10.4}; ORFNames=T04C10.4 {ECO:0000312|WormBase:T04C10.4};
• Organism (full): Caenorhabditis elegans.
• Protein Family: Belongs to the bZIP family. .
• Key Domains: bZIP. (IPR004827); bZIP_sf. (IPR046347); bZIP_1 (PF00170)

MANDATORY VERIFICATION STEPS:

1. Check if the gene symbol "atf-4" matches the protein description above
2. Verify the organism is correct: Caenorhabditis elegans.
3. Check if protein family/domains align with what you find in literature
4. If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'atf-4' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene atf-4 (gene ID: atf-4, UniProt: Q22156) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

• UniProt Accession: Q22156
• Protein Description: RecName: Full=Transcription factor atf-4 homolog {ECO:0000303|PubMed:35181679}; AltName: Full=cAMP-dependent transcription factor family member 4 {ECO:0000312|WormBase:T04C10.4};
• Gene Information: Name=atf-4 {ECO:0000312|WormBase:T04C10.4}; Synonyms=atf-5 {ECO:0000312|WormBase:T04C10.4}; ORFNames=T04C10.4 {ECO:0000312|WormBase:T04C10.4};
• Organism (full): Caenorhabditis elegans.
• Protein Family: Belongs to the bZIP family. .
• Key Domains: bZIP. (IPR004827); bZIP_sf. (IPR046347); bZIP_1 (PF00170)

MANDATORY VERIFICATION STEPS:

1. Check if the gene symbol "atf-4" matches the protein description above
2. Verify the organism is correct: Caenorhabditis elegans.
3. Check if protein family/domains align with what you find in literature
4. If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'atf-4' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene atf-4 (gene ID: atf-4, UniProt: Q22156) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Title: Functional annotation of C. elegans atf-4 (T04C10.4; UniProt Q22156)

Abstract
We review current knowledge on the Caenorhabditis elegans atf-4 gene product (UniProt Q22156), a basic leucine zipper (bZIP) transcription factor and ortholog of mammalian ATF4. We verify its identity and organismal context, summarize integrated stress response (ISR)-linked translational regulation via upstream open reading frames (uORFs), define its molecular and cellular functions, delineate downstream pathways (notably the ATF-4→cth-2→H2S axis), synthesize quantitative data on longevity and stress phenotypes, and highlight recent advances and translational implications. Where available, URLs and publication dates are provided; citations follow each claim.

Plan and verification
- Identity verification: The C. elegans gene symbol atf-4 corresponds to locus T04C10.4 and encodes a bZIP transcription factor, consistent with UniProt Q22156. Worm studies use atf-4(tm4397) mutants, a Patf-4(uORF)::GFP translational reporter, and Patf-4::ATF-4::GFP transgenes, confirming correct gene/protein identity in C. elegans (Nature Communications; Feb 2022; https://doi.org/10.1038/s41467-022-28599-9). The gene was previously referred to as atf-5 in some worm literature but corresponds to the ATF4 ortholog (statzer2022atf4andhydrogen pages 11-11, statzer2022atf4andhydrogen pages 3-4, statzer2022atf4andhydrogen pages 4-5).

1) Key concepts and definitions
- atf-4 encodes a stress-inducible, nuclear bZIP transcription factor that functions as a central ISR effector in eukaryotes. In C. elegans, atf-4 (T04C10.4) is preferentially translated under reduced global protein synthesis and coordinates transcriptional programs that enhance proteostasis, stress resistance, and longevity (Nature Communications; Feb 2022; https://doi.org/10.1038/s41467-022-28599-9) (statzer2022atf4andhydrogen pages 1-2, statzer2022atf4andhydrogen pages 3-4, statzer2022atf4andhydrogen pages 4-5).
- ISR-linked translational control: atf-4 mRNA harbors two 5′ UTR uORFs that normally suppress main-ORF translation; when global initiation is reduced (e.g., by translation or mTORC1 inhibition), scanning ribosomes bypass uORF repression, selectively increasing ATF-4 synthesis. This was demonstrated using a Patf-4(uORF)::GFP reporter, ribosome profiling, and pharmacologic perturbations (cycloheximide, tunicamycin) (Nature Communications; Feb 2022; https://doi.org/10.1038/s41467-022-28599-9) (statzer2022atf4andhydrogen pages 3-4, statzer2022atf4andhydrogen pages 1-2, statzer2022atf4andhydrogen pages 4-4).

2) Recent developments and latest research (prioritized 2023–2024)
- Contemporary expert synthesis (2023): A review of ATF4 regulation and ISR outcomes consolidates mechanistic understanding of eIF2α kinase activation and the uORF-based translational logic that applies across species, informing interpretation of worm ATF-4 induction and target programs (Frontiers in Molecular Neuroscience; Feb 2023; https://doi.org/10.3389/fnmol.2023.1112253) (gotz2025suppressionratherthan pages 1-5).
- GCN2/ISR as a therapeutic axis (2024): A focused review highlights GCN2-eIF2α-ATF4 as a druggable node in age-related disease, reinforcing translational relevance of ATF-4 pathways uncovered in worms (Frontiers in Aging; Sep 2024; https://doi.org/10.3389/fragi.2024.1447370) (gotz2025suppressionratherthan pages 23-26, gotz2025suppressionratherthan pages 30-33).
- Although outside worms, these 2023–2024 sources align with worm mechanistic data and support the generalizability of ISR-ATF4 biology relevant to atf-4 (gotz2025suppressionratherthan pages 23-26, gotz2025suppressionratherthan pages 30-33, gotz2025suppressionratherthan pages 1-5).

3) Molecular function, localization, and pathway context in C. elegans
- Molecular function: ATF-4 acts as a transcriptional activator of cytoprotective and proteostasis genes. ATF-4 overexpression (Patf-4::ATF-4::GFP) upregulates small heat-shock/chaperone genes (e.g., sip-1/CRYAA, hsp-70, hsp-16.2, hsp-12.3) and other stress-response targets; several of these are required for ATF-4-driven lifespan extension, indicating a direct functional role in proteostasis (Nature Communications; Feb 2022; https://doi.org/10.1038/s41467-022-28599-9) (statzer2022atf4andhydrogen pages 4-5).
- Subcellular localization: ATF-4::GFP localizes to nuclei in neuronal, hypodermal, and other somatic tissues upon overexpression, consistent with its role as a transcription factor acting in the nucleus (Nature Communications; Feb 2022; https://doi.org/10.1038/s41467-022-28599-9) (statzer2022atf4andhydrogen pages 3-4, statzer2022atf4andhydrogen pages 4-5).
- ISR and eIF2α: Tunicamycin robustly increases eIF2α phosphorylation and induces the atf-4 reporter and ATF-4 protein, whereas short cycloheximide treatment increases the atf-4 reporter with minimal eIF2α phosphorylation, indicating that reduced global translation alone can elevate ATF-4 translation. Notably, an eIF2α phosphorylation-defective mutant (y37e3.10(qd338)) still permits ifg-1(RNAi)-mediated, atf-4-dependent lifespan extension, establishing that some ATF-4 activation and longevity outputs can be ISR-independent in worms (Nature Communications; Feb 2022; https://doi.org/10.1038/s41467-022-28599-9) (statzer2022atf4andhydrogen pages 4-4, statzer2022atf4andhydrogen pages 3-4).

4) Downstream pathways and gene programs
- ATF-4→cth-2→H2S axis: ATF-4 induces the transsulfuration enzyme cth-2, increasing hydrogen sulfide (H2S) production capacity and elevating protein persulfidation (PSSH), a protective cysteine modification. Genetic data show that cth-2 knockdown ablates longevity and stress resistance from mTORC1 pathway inhibition (e.g., raga-1), placing cth-2 downstream of ATF-4 in longevity control (Nature Communications; Feb 2022; https://doi.org/10.1038/s41467-022-28599-9) (statzer2022atf4andhydrogen pages 8-9, statzer2022atf4andhydrogen pages 9-11).
- Network cooperation: ATF-4-driven longevity requires canonical longevity transcription factors—DAF-16/FOXO, HSF-1/HSF, and SKN-1/NRF—indicating interdependent transcriptional networks governing proteostasis and stress responses (Nature Communications; Feb 2022; https://doi.org/10.1038/s41467-022-28599-9) (statzer2022atf4andhydrogen pages 4-5).

5) Roles in stress responses, immunity, and longevity, with quantitative data
- Longevity sufficiency: ATF-4 overexpression is sufficient to extend lifespan by approximately 7–44% across more than 10 independent trials and to improve healthspan (increased late-life pharyngeal pumping), establishing ATF-4 as a potent longevity factor in worms (Nature Communications; Feb 2022; https://doi.org/10.1038/s41467-022-28599-9) (statzer2022atf4andhydrogen pages 3-4, statzer2022atf4andhydrogen pages 4-5).
- Longevity necessity under translation suppression: Adult-specific reduction of global translation by ifg-1(RNAi) or short cycloheximide exposure extends lifespan in wild-type but not in atf-4 mutants, demonstrating that ATF-4 is required for longevity benefits from translation attenuation (Nature Communications; Feb 2022; https://doi.org/10.1038/s41467-022-28599-9) (statzer2022atf4andhydrogen pages 4-4).
- Reporter induction and protein levels: Tunicamycin (35 μg/ml, 4 h) approximately doubles ATF-4 protein in L4 animals; atf-4 mRNA increases only ~1.5-fold, and induction of the Patf-4(uORF)::GFP reporter persists when transcription is blocked by α-amanitin, supporting translational control via uORFs (Nature Communications; Feb 2022; https://doi.org/10.1038/s41467-022-28599-9) (statzer2022atf4andhydrogen pages 3-4, statzer2022atf4andhydrogen pages 1-2).

6) Current applications and real-world implementations
- Pharmacologic triggers used in worms: Translation/ER stress modulators (cycloheximide and tunicamycin) and rapamycin (mTOR inhibitor) have been used to manipulate ATF-4 translation and/or reporter activity in C. elegans. Rapamycin increases the atf-4 uORF reporter, although rapamycin-induced lifespan extension can be ATF-4–independent in some contexts, indicating pathway- and context-specific roles (Nature Communications; Feb 2022; https://doi.org/10.1038/s41467-022-28599-9) (statzer2022atf4andhydrogen pages 3-4, statzer2022atf4andhydrogen pages 1-2, statzer2022atf4andhydrogen pages 4-4).
- Therapeutic implications: The worm ATF-4→cth-2→H2S pathway suggests that boosting H2S production or enhancing protein persulfidation could capture benefits of ISR/translation suppression without broad proteostasis disruption, consistent with translational interest in H2S donors under clinical investigation (as noted in the 2022 worm study) and reviews emphasizing ISR nodes as therapeutic targets (Nature Communications; Feb 2022; https://doi.org/10.1038/s41467-022-28599-9; Frontiers in Aging; Sep 2024; https://doi.org/10.3389/fragi.2024.1447370) (statzer2022atf4andhydrogen pages 11-11, gotz2025suppressionratherthan pages 23-26).

7) Expert opinions and integrative analysis
- Cross-species ISR logic: Reviews emphasize that eIF2α phosphorylation by stress-sensing kinases lowers global initiation while selectively enabling ATF4 translation via uORFs, a logic recapitulated by worm atf-4 reporters and ribosome profiling (Frontiers in Molecular Neuroscience; Feb 2023; https://doi.org/10.3389/fnmol.2023.1112253). Worm experiments further show that ATF-4 can be preferentially translated without detectable eIF2α phosphorylation under some translation-limiting conditions (e.g., ifg-1 depletion), underscoring parallel entry points into ATF-4 induction (gotz2025suppressionratherthan pages 1-5, statzer2022atf4andhydrogen pages 4-4).
- Longevity mechanisms: Worm data position ATF-4 as an integration node for translational and mTORC1 signals that converge on proteostasis (chaperones) and sulfur metabolism (cth-2/H2S), acting with DAF-16, HSF-1, and SKN-1 to enhance stress resistance and healthspan (Nature Communications; Feb 2022; https://doi.org/10.1038/s41467-022-28599-9) (statzer2022atf4andhydrogen pages 4-5).

8) Summary statistics and data points
- Lifespan extension by ATF-4 overexpression: ~7–44% across >10 independent trials; improved late-life pumping (Nature Communications; Feb 2022; https://doi.org/10.1038/s41467-022-28599-9) (statzer2022atf4andhydrogen pages 3-4, statzer2022atf4andhydrogen pages 4-5).
- Reporter/protein induction under stress: Tunicamycin (35 μg/ml, 4 h) roughly doubles ATF-4 protein; atf-4 mRNA increases ~1.5×; cycloheximide (7.2 mM, 1 h) robustly increases the Patf-4(uORF)::GFP translational reporter (Nature Communications; Feb 2022; https://doi.org/10.1038/s41467-022-28599-9) (statzer2022atf4andhydrogen pages 3-4, statzer2022atf4andhydrogen pages 1-2).
- eIF2α phosphorylation: Strongly increased by tunicamycin; minimally affected by short cycloheximide, illustrating differential ISR engagement (Nature Communications; Feb 2022; https://doi.org/10.1038/s41467-022-28599-9) (statzer2022atf4andhydrogen pages 4-4).

Embedded summary table
| Area | Specific finding | Experimental support (methods/constructs) | Quantitative notes | Source (DOI/URL) | Date | Context ID |
|---|---|---|---|---|---|---|
| Identity | atf-4 (T04C10.4), 208 aa; bZIP transcription factor (ortholog of mammalian ATF4; formerly atf-5) | Gene/protein annotation and transgenic constructs: Patf-4::ATF-4::GFP (pWM48), atf-4(tm4397) mutant; reported protein length and locus information | — | https://doi.org/10.1038/s41467-022-28599-9 | Feb 2022 | (statzer2022atf4andhydrogen pages 11-11, statzer2022atf4andhydrogen pages 4-5) |
| ISR mechanism (uORF/eIF2α) | atf-4 contains two 5' UTR uORFs; preferential translation of main ORF when global translation is reduced; Patf-4(uORF)::GFP reporter induced post-transcriptionally (reporter induction persists with transcription blocked) | Patf-4(uORF)::GFP reporter (LD1499), ribosome profiling (SRA dataset), α-amanitin pre-treatment, puromycin incorporation assays | TM increased atf-4 mRNA ~1.5-fold; tunicamycin doubled ATF-4 protein; CHX (7.2 mM, 1 h) increased reporter; ifg-1 RNAi strongly increased reporter | https://doi.org/10.1038/s41467-022-28599-9 | Feb 2022 | (statzer2022atf4andhydrogen pages 3-4, statzer2022atf4andhydrogen pages 4-4, statzer2022atf4andhydrogen pages 1-2) |
| Roles in longevity & proteostasis | ATF-4 overexpression (ATF-4OE) is sufficient to extend lifespan and improve healthspan; upregulates small heat-shock/chaperone genes and proteostasis factors | ATF-4OE transgenic lines (wbmEx26, ldIs119), RNA-seq, qRT-PCR, Kaplan–Meier lifespan assays (with FUdR), pharyngeal pumping assays | Lifespan extension by ATF-4OE: ~7–44% across >10 trials; increased pharyngeal pumping at day 10; rapid increase in translation of atf-4 after heat shock | https://doi.org/10.1038/s41467-022-28599-9 | Feb 2022 | (statzer2022atf4andhydrogen pages 3-4, statzer2022atf4andhydrogen pages 4-5) |
| Downstream cth-2 / H2S axis & persulfidation | ATF-4 activates cth-2 (cystathionine γ-lyase) → increased H2S production capacity and elevated protein persulfidation (PSSH); cth-2 required for lifespan extension from mTORC1 inhibition | Genetic perturbations: raga-1, rict-1 RNAi/mutants; cth-2 knockdown/mutants; biochemical H2S production assays; persulfidation detection assays | cth-2 knockdown ablates raga-1(mediated) longevity; persulfidation levels increased with ATF-4OE and decreased in cth-2 or atf-4 mutants (statistical differences reported in paper figures) | https://doi.org/10.1038/s41467-022-28599-9 | Feb 2022 | (statzer2022atf4andhydrogen pages 8-9, statzer2022atf4andhydrogen pages 9-11) |
| Genetic dependencies & eIF2α note | ATF-4–driven longevity requires hsf-1, skn-1, and daf-16 (knockdown abolishes ATF-4OE benefit); however, some ATF-4 activation and lifespan effects from translation reduction can occur independently of canonical eIF2α phosphorylation | RNAi knockdowns (hsf-1, skn-1, daf-16), eif-2α phosphorylation-defective mutant y37e3.10(qd338), ifg-1 RNAi lifespan assays | Tunicamycin strongly increases eIF2α phosphorylation, but short CHX treatment did not; eif-2α(qd338) did not prevent lifespan extension caused by ifg-1 knockdown, indicating eIF2α-phospho–independent atf-4 activation routes | https://doi.org/10.1038/s41467-022-28599-9 | Feb 2022 | (statzer2022atf4andhydrogen pages 4-5, statzer2022atf4andhydrogen pages 3-4, statzer2022atf4andhydrogen pages 4-4) |
| Subcellular localization (reporter) | ATF-4::GFP shows nuclear accumulation in neuronal, hypodermal and somatic tissues when overexpressed | Fluorescence imaging of Patf-4::ATF-4::GFP transgenics (ldIs119, wbmEx26) and Patf-4(uORF)::GFP reporter lines | Observed nuclear localization in multiple somatic tissues by GFP; reporter induction spatially resolved in imaging | https://doi.org/10.1038/s41467-022-28599-9 | Feb 2022 | (statzer2022atf4andhydrogen pages 3-4, statzer2022atf4andhydrogen pages 4-5) |
| Pharmacologic triggers & assays | Translation/ER stress modulators induce Patf-4 reporters and ATF-4 protein; rapamycin increases reporter but ATF-4 is not always required for rapamycin lifespan effects | Treatments: cycloheximide (CHX), tunicamycin (TM), rapamycin; puromycin incorporation to measure global translation; lifespan assays with drug treatments | CHX 7.2 mM (1 h) increases Patf-4 reporter; TM 35 µg/ml (4 h) doubled ATF-4 protein; puromycin assay used (0.5 mg/ml, 1 h) to measure translation changes; rapamycin increased reporter but rapamycin-mediated lifespan extension can be ATF-4–independent | https://doi.org/10.1038/s41467-022-28599-9 | Feb 2022 | (statzer2022atf4andhydrogen pages 3-4, statzer2022atf4andhydrogen pages 1-2, statzer2022atf4andhydrogen pages 4-4) |

Table: Concise table of key, evidence-backed findings for C. elegans atf-4 (T04C10.4) from Statzer et al. (Nature Communications), including identity, ISR mechanism, functional roles, downstream H2S axis, genetic dependencies, localization, and pharmacologic triggers. Useful as a quick reference linking experimental methods, quantitative notes, DOI, date, and context IDs for follow-up.

Conclusions
C. elegans atf-4 (T04C10.4; bZIP) is a validated ATF4 ortholog that integrates translational and stress signals via uORF-mediated translational control to drive nuclear transcriptional programs enhancing proteostasis and longevity. A key downstream effector is cth-2, which elevates H2S production and protein persulfidation, and ATF-4 acts cooperatively with DAF-16, HSF-1, and SKN-1. ATF-4 sufficiency for lifespan extension (7–44%) and its necessity for longevity from translation suppression establish it as a central node in worm longevity circuits. Pharmacologic manipulation of translation, ER stress, or mTORC1 modulates ATF-4 reporters and phenotypes, suggesting translational potential for H2S-centric or ISR-targeted interventions. These findings provide a precise functional annotation of atf-4 in worms and a framework for targeted modulation in aging and stress biology (statzer2022atf4andhydrogen pages 8-9, statzer2022atf4andhydrogen pages 3-4, statzer2022atf4andhydrogen pages 1-2, statzer2022atf4andhydrogen pages 4-4, statzer2022atf4andhydrogen pages 4-5).

References

1. (statzer2022atf4andhydrogen pages 11-11): Cyril Statzer, Jin Meng, Richard Venz, Monet Bland, Stacey Robida-Stubbs, Krina Patel, Dunja Petrovic, Raffaella Emsley, Pengpeng Liu, Ianessa Morantte, Cole Haynes, William B. Mair, Alban Longchamp, Milos R. Filipovic, T. Keith Blackwell, and Collin Y. Ewald. Atf-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mtorc1. Nature Communications, Feb 2022. URL: https://doi.org/10.1038/s41467-022-28599-9, doi:10.1038/s41467-022-28599-9. This article has 84 citations and is from a highest quality peer-reviewed journal.

2. (statzer2022atf4andhydrogen pages 3-4): Cyril Statzer, Jin Meng, Richard Venz, Monet Bland, Stacey Robida-Stubbs, Krina Patel, Dunja Petrovic, Raffaella Emsley, Pengpeng Liu, Ianessa Morantte, Cole Haynes, William B. Mair, Alban Longchamp, Milos R. Filipovic, T. Keith Blackwell, and Collin Y. Ewald. Atf-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mtorc1. Nature Communications, Feb 2022. URL: https://doi.org/10.1038/s41467-022-28599-9, doi:10.1038/s41467-022-28599-9. This article has 84 citations and is from a highest quality peer-reviewed journal.

3. (statzer2022atf4andhydrogen pages 4-5): Cyril Statzer, Jin Meng, Richard Venz, Monet Bland, Stacey Robida-Stubbs, Krina Patel, Dunja Petrovic, Raffaella Emsley, Pengpeng Liu, Ianessa Morantte, Cole Haynes, William B. Mair, Alban Longchamp, Milos R. Filipovic, T. Keith Blackwell, and Collin Y. Ewald. Atf-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mtorc1. Nature Communications, Feb 2022. URL: https://doi.org/10.1038/s41467-022-28599-9, doi:10.1038/s41467-022-28599-9. This article has 84 citations and is from a highest quality peer-reviewed journal.

4. (statzer2022atf4andhydrogen pages 1-2): Cyril Statzer, Jin Meng, Richard Venz, Monet Bland, Stacey Robida-Stubbs, Krina Patel, Dunja Petrovic, Raffaella Emsley, Pengpeng Liu, Ianessa Morantte, Cole Haynes, William B. Mair, Alban Longchamp, Milos R. Filipovic, T. Keith Blackwell, and Collin Y. Ewald. Atf-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mtorc1. Nature Communications, Feb 2022. URL: https://doi.org/10.1038/s41467-022-28599-9, doi:10.1038/s41467-022-28599-9. This article has 84 citations and is from a highest quality peer-reviewed journal.

5. (statzer2022atf4andhydrogen pages 4-4): Cyril Statzer, Jin Meng, Richard Venz, Monet Bland, Stacey Robida-Stubbs, Krina Patel, Dunja Petrovic, Raffaella Emsley, Pengpeng Liu, Ianessa Morantte, Cole Haynes, William B. Mair, Alban Longchamp, Milos R. Filipovic, T. Keith Blackwell, and Collin Y. Ewald. Atf-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mtorc1. Nature Communications, Feb 2022. URL: https://doi.org/10.1038/s41467-022-28599-9, doi:10.1038/s41467-022-28599-9. This article has 84 citations and is from a highest quality peer-reviewed journal.

6. (gotz2025suppressionratherthan pages 1-5): Miriam S Götz, Dan J. Hayman, Gracie Adams, Fumiaki Obata, and Mirre J P Simons. Suppression rather than activation of the integrated-stress-response (gcn2-atf4) pathway extends lifespan in the fly. BioRxiv, Jul 2025. URL: https://doi.org/10.1101/2025.07.14.664701, doi:10.1101/2025.07.14.664701. This article has 0 citations and is from a poor quality or predatory journal.

7. (gotz2025suppressionratherthan pages 23-26): Miriam S Götz, Dan J. Hayman, Gracie Adams, Fumiaki Obata, and Mirre J P Simons. Suppression rather than activation of the integrated-stress-response (gcn2-atf4) pathway extends lifespan in the fly. BioRxiv, Jul 2025. URL: https://doi.org/10.1101/2025.07.14.664701, doi:10.1101/2025.07.14.664701. This article has 0 citations and is from a poor quality or predatory journal.

8. (gotz2025suppressionratherthan pages 30-33): Miriam S Götz, Dan J. Hayman, Gracie Adams, Fumiaki Obata, and Mirre J P Simons. Suppression rather than activation of the integrated-stress-response (gcn2-atf4) pathway extends lifespan in the fly. BioRxiv, Jul 2025. URL: https://doi.org/10.1101/2025.07.14.664701, doi:10.1101/2025.07.14.664701. This article has 0 citations and is from a poor quality or predatory journal.

9. (statzer2022atf4andhydrogen pages 8-9): Cyril Statzer, Jin Meng, Richard Venz, Monet Bland, Stacey Robida-Stubbs, Krina Patel, Dunja Petrovic, Raffaella Emsley, Pengpeng Liu, Ianessa Morantte, Cole Haynes, William B. Mair, Alban Longchamp, Milos R. Filipovic, T. Keith Blackwell, and Collin Y. Ewald. Atf-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mtorc1. Nature Communications, Feb 2022. URL: https://doi.org/10.1038/s41467-022-28599-9, doi:10.1038/s41467-022-28599-9. This article has 84 citations and is from a highest quality peer-reviewed journal.

10. (statzer2022atf4andhydrogen pages 9-11): Cyril Statzer, Jin Meng, Richard Venz, Monet Bland, Stacey Robida-Stubbs, Krina Patel, Dunja Petrovic, Raffaella Emsley, Pengpeng Liu, Ianessa Morantte, Cole Haynes, William B. Mair, Alban Longchamp, Milos R. Filipovic, T. Keith Blackwell, and Collin Y. Ewald. Atf-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mtorc1. Nature Communications, Feb 2022. URL: https://doi.org/10.1038/s41467-022-28599-9, doi:10.1038/s41467-022-28599-9. This article has 84 citations and is from a highest quality peer-reviewed journal.

Citations

1. gotz2025suppressionratherthan pages 1-5
2. gotz2025suppressionratherthan pages 23-26
3. gotz2025suppressionratherthan pages 30-33
4. https://doi.org/10.1038/s41467-022-28599-9
5. https://doi.org/10.3389/fnmol.2023.1112253
6. https://doi.org/10.3389/fragi.2024.1447370
7. https://doi.org/10.1038/s41467-022-28599-9;
8. https://doi.org/10.1038/s41467-022-28599-9,
9. https://doi.org/10.1101/2025.07.14.664701,