Spermidine

evidence_access

Primary full text

experimental_model

Yeast strains with synthesis/interconversion deletions and reporter modeling.

limitations

Do not transfer the quantitative yeast response to human OAZ1.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Polyamine abundance feeds back into synthesis control.

primary_references

Translational recoding as a feedback controller: systems approaches reveal polyamine-specific effects on the antizyme ribosomal frameshift. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21303766/ · DOI 10.1093/nar/gkq1349

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Yeast strains with synthesis/interconversion deletions and reporter modeling. · source_derived_draft · unverified_draft

## spermidine-antizyme-feedback Polyamine abundance feeds back into synthesis control. Spermidine stimulated OAZ1 +1 frameshifting in engineered yeast; its response lacked the cooperativity seen with putrescine and spermine. Model: Yeast strains with synthesis/interconversion deletions and reporter modeling. Limitations: Do not transfer the quantitative yeast response to human OAZ1. Evidence access: Primary full text Translational recoding as a feedback controller: systems approaches reveal polyamine-specific effects on the antizyme ribosomal frameshift. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21303766/ · DOI 10.1093/nar/gkq1349

evidence_access

Primary abstract

experimental_model

Cultured human cells; pharmacological compound comparison.

limitations

Flux markers require their assay controls; not evidence of human lifespan extension.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

The cell’s recycling response increased in this experiment.

primary_references

Spermidine induces autophagy by inhibiting the acetyltransferase EP300. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25526088/ · DOI 10.1038/cdd.2014.215

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cultured human cells; pharmacological compound comparison. · source_derived_draft · unverified_draft

## spermidine-autophagic-flux The cell’s recycling response increased in this experiment. Spermidine induced autophagic-flux markers, including GFP-LC3 puncta and p62 depletion, in cultured human cells. Model: Cultured human cells; pharmacological compound comparison. Limitations: Flux markers require their assay controls; not evidence of human lifespan extension. Evidence access: Primary abstract Spermidine induces autophagy by inhibiting the acetyltransferase EP300. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25526088/ · DOI 10.1038/cdd.2014.215

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Primary human B cells from older donors.

limitations

Not an oral vaccine-efficacy trial or proof of whole-body immune rejuvenation.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Older immune cells responded in culture.

primary_references

Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31474573/ · DOI 10.1016/j.molcel.2019.08.005

trigger_kind

biomarker_context Imported condition classification; unverified.

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary human B cells from older donors. · source_derived_draft · unverified_draft

## spermidine-bcell-human Older immune cells responded in culture. Spermidine supplementation restored the hypusination–TFEB–autophagy pathway and improved old-donor B-cell responses ex vivo. Model: Primary human B cells from older donors. Limitations: Not an oral vaccine-efficacy trial or proof of whole-body immune rejuvenation. Evidence access: Primary full text Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31474573/ · DOI 10.1016/j.molcel.2019.08.005

evidence_access

Primary full text

experimental_model

Recombinant human DHPS; assay-dependent apparent affinity.

limitations

Binding affinity is not a dietary requirement, plasma target or treatment dose.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

The first enzyme recognizes spermidine directly.

primary_references

Half Way to Hypusine-Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32235505/ · DOI 10.3390/biom10040522

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human DHPS; assay-dependent apparent affinity. · source_derived_draft · unverified_draft

## spermidine-dhps-binding The first enzyme recognizes spermidine directly. The human DHPS study measured an apparent spermidine binding KD of about 4 micromolar using the reported FRET assay. Model: Recombinant human DHPS; assay-dependent apparent affinity. Limitations: Binding affinity is not a dietary requirement, plasma target or treatment dose. Evidence access: Primary full text Half Way to Hypusine-Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32235505/ · DOI 10.3390/biom10040522

evidence_access

Primary abstract

experimental_model

Rat testis enzyme; comparative polyamine inhibition kinetics.

limitations

High-concentration enzyme inhibition is not a contradiction of cellular hypusination rescue; no human inhibitory threshold established.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

More substrate upstream does not guarantee more activity downstream.

primary_references

Inhibition of deoxyhypusine hydroxylase by polyamines and by a deoxyhypusine peptide. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2765563/ · DOI 10.1016/0167-4838(89)90195-7

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat testis enzyme; comparative polyamine inhibition kinetics. · source_derived_draft · unverified_draft

## spermidine-dohh-high-polyamine More substrate upstream does not guarantee more activity downstream. Spermidine inhibited rat-testis deoxyhypusine hydroxylase in vitro, less potently than spermine. Model: Rat testis enzyme; comparative polyamine inhibition kinetics. Limitations: High-concentration enzyme inhibition is not a contradiction of cellular hypusination rescue; no human inhibitory threshold established. Evidence access: Primary abstract Inhibition of deoxyhypusine hydroxylase by polyamines and by a deoxyhypusine peptide. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2765563/ · DOI 10.1016/0167-4838(89)90195-7

evidence_access

Primary abstract

experimental_model

Recombinant human EP300 assay with companion human-cell experiments.

limitations

Biochemical inhibition is not proof of selective target engagement after dietary exposure.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

One route changes protein acetylation.

primary_references

Spermidine induces autophagy by inhibiting the acetyltransferase EP300. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25526088/ · DOI 10.1038/cdd.2014.215

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human EP300 assay with companion human-cell experiments. · source_derived_draft · unverified_draft

## spermidine-ep300 One route changes protein acetylation. Spermidine inhibited acetyltransferase activity of recombinant EP300 in vitro. Model: Recombinant human EP300 assay with companion human-cell experiments. Limitations: Biochemical inhibition is not proof of selective target engagement after dietary exposure. Evidence access: Primary abstract Spermidine induces autophagy by inhibiting the acetyltransferase EP300. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25526088/ · DOI 10.1038/cdd.2014.215

evidence_access

Primary full text

experimental_model

Human prostate cancer cells; 1.25–5 micromolar erastin, 24-hour viability assays.

limitations

Not evidence of cancer prevention or a safe self-treatment combination.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A cancer-cell context can turn the response toward iron-dependent injury.

primary_references

Spermidine inactivates proteasome activity and enhances ferroptosis in prostate cancer. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40486852/ · DOI 10.1016/j.apsb.2025.02.023

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human prostate cancer cells; 1.25–5 micromolar erastin, 24-hour viability assays. · source_derived_draft · unverified_draft

## spermidine-erastin-sensitization A cancer-cell context can turn the response toward iron-dependent injury. One micromolar spermidine enhanced erastin-associated lipid peroxidation and cell death in PC3 and DU145 cells. Model: Human prostate cancer cells; 1.25–5 micromolar erastin, 24-hour viability assays. Limitations: Not evidence of cancer prevention or a safe self-treatment combination. Evidence access: Primary full text Spermidine inactivates proteasome activity and enhances ferroptosis in prostate cancer. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40486852/ · DOI 10.1016/j.apsb.2025.02.023

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human U2OS/H4 cells; 10 micromolar spermidine, with 1 mM aminoguanidine in rescue conditions.

limitations

Serum-oxidase control matters; supplementation did not further raise flux in already-starved intact U2OS cells.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Replacing the missing metabolite restored a response.

primary_references

Spermidine is essential for fasting-mediated autophagy and longevity. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39117797/ · DOI 10.1038/s41556-024-01468-x

trigger_kind

machinery_impairment Imported condition classification; unverified.

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human U2OS/H4 cells; 10 micromolar spermidine, with 1 mM aminoguanidine in rescue conditions. · source_derived_draft · unverified_draft

## spermidine-fasting-rescue Replacing the missing metabolite restored a response. Added spermidine rescued autophagic-flux suppression caused by DFMO during starvation. Model: Human U2OS/H4 cells; 10 micromolar spermidine, with 1 mM aminoguanidine in rescue conditions. Limitations: Serum-oxidase control matters; supplementation did not further raise flux in already-starved intact U2OS cells. Evidence access: Primary full text Spermidine is essential for fasting-mediated autophagy and longevity. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39117797/ · DOI 10.1038/s41556-024-01468-x

evidence_access

Primary full text

experimental_model

Caco-2 and patient-derived macrophage cocultures; 100 micromolar spermidine, 24 hours.

limitations

Ex-vivo barrier readouts do not establish oral treatment efficacy for IBD.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Human cells allow a more direct test of the barrier pathway.

primary_references

Spermidine Ameliorates Colitis via Induction of Anti-Inflammatory Macrophages and Prevention of Intestinal Dysbiosis. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36995738/ · DOI 10.1093/ecco-jcc/jjad058

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Caco-2 and patient-derived macrophage cocultures; 100 micromolar spermidine, 24 hours. · source_derived_draft · unverified_draft

## spermidine-gut-human-barrier Human cells allow a more direct test of the barrier pathway. Spermidine preserved barrier readouts in LPS-challenged epithelial–macrophage cocultures in a PTPN2-dependent setting. Model: Caco-2 and patient-derived macrophage cocultures; 100 micromolar spermidine, 24 hours. Limitations: Ex-vivo barrier readouts do not establish oral treatment efficacy for IBD. Evidence access: Primary full text Spermidine Ameliorates Colitis via Induction of Anti-Inflammatory Macrophages and Prevention of Intestinal Dysbiosis. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36995738/ · DOI 10.1093/ecco-jcc/jjad058

evidence_access

Primary abstract

experimental_model

Aging mice receiving spermidine in drinking water.

limitations

Not a clinical cardiac-treatment trial; separate downstream mechanisms remain model dependent.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Several measured cardiac maintenance processes changed.

primary_references

Cardioprotection and lifespan extension by the natural polyamine spermidine. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27841876/ · DOI 10.1038/nm.4222

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Aging mice receiving spermidine in drinking water. · source_derived_draft · unverified_draft

## spermidine-heart-autophagy Several measured cardiac maintenance processes changed. Oral spermidine enhanced cardiac autophagy, mitophagy and mitochondrial respiration in the mouse aging study. Model: Aging mice receiving spermidine in drinking water. Limitations: Not a clinical cardiac-treatment trial; separate downstream mechanisms remain model dependent. Evidence access: Primary abstract Cardioprotection and lifespan extension by the natural polyamine spermidine. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27841876/ · DOI 10.1038/nm.4222

evidence_access

Primary full text

experimental_model

100 adults aged 60–90 with subjective cognitive decline; randomized trial.

limitations

Extract rather than pure spermidine; dose and population specific. Difference -0.03, 95% CI -0.11 to 0.05, P=.47.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

The longer human trial did not confirm its main memory hypothesis.

primary_references

Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline: A Randomized Clinical Trial. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35616942/ · DOI 10.1001/jamanetworkopen.2022.13875

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 100 adults aged 60–90 with subjective cognitive decline; randomized trial. · source_derived_draft · unverified_draft

## spermidine-human-memory-null The longer human trial did not confirm its main memory hypothesis. Twelve months of wheat-germ extract supplying 0.9 mg/day spermidine did not significantly improve the primary memory outcome versus placebo. Model: 100 adults aged 60–90 with subjective cognitive decline; randomized trial. Limitations: Extract rather than pure spermidine; dose and population specific. Difference -0.03, 95% CI -0.11 to 0.05, P=.47. Evidence access: Primary full text Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline: A Randomized Clinical Trial. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35616942/ · DOI 10.1001/jamanetworkopen.2022.13875

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Twelve healthy adults; blinded randomized crossover pharmacokinetic study.

limitations

Short study and plasma sampling do not exclude intracellular changes, other regimens or long-term effects.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Swallowing more did not measurably raise this plasma pool.

primary_references

High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37111071/ · DOI 10.3390/nu15081852

trigger_kind

biomarker_context Imported condition classification; unverified.

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Twelve healthy adults; blinded randomized crossover pharmacokinetic study. · source_derived_draft · unverified_draft

## spermidine-human-plasma-null Swallowing more did not measurably raise this plasma pool. Oral 15 mg/day spermidine for five days did not significantly increase plasma spermidine or putrescine versus placebo. Model: Twelve healthy adults; blinded randomized crossover pharmacokinetic study. Limitations: Short study and plasma sampling do not exclude intracellular changes, other regimens or long-term effects. Evidence access: Primary full text High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37111071/ · DOI 10.3390/nu15081852

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Twelve-person crossover trial; 15 mg/day, five days.

limitations

Presystemic conversion was an interpretation, not proven by an isotope tracer; the fasting spermine comparison was not significant.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A related metabolite changed instead.

primary_references

High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37111071/ · DOI 10.3390/nu15081852

trigger_kind

biomarker_context Imported condition classification; unverified.

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 558–564

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Twelve-person crossover trial; 15 mg/day, five days. · source_derived_draft · unverified_draft

## spermidine-human-spermine A related metabolite changed instead. The same trial found increased plasma spermine exposure after oral spermidine. Model: Twelve-person crossover trial; 15 mg/day, five days. Limitations: Presystemic conversion was an interpretation, not proven by an isotope tracer; the fasting spermine comparison was not significant. Evidence access: Primary full text High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37111071/ · DOI 10.3390/nu15081852

evidence_access

Primary abstract

experimental_model

Xenopus oocyte inside-out patches; construct species unresolved in accessed abstract.

limitations

Do not relabel the channel as a verified human isoform or infer a serum-potassium effect.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Spermidine can limit outward potassium current.

primary_references

The mechanism of inward rectification of potassium channels: "long-pore plugging" by cytoplasmic polyamines. · 1995 · https://pubmed.ncbi.nlm.nih.gov/8648298/ · DOI 10.1085/jgp.106.5.923

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Xenopus oocyte inside-out patches; construct species unresolved in accessed abstract. · source_derived_draft · unverified_draft

## spermidine-kir-block Spermidine can limit outward potassium current. Cytoplasmic spermidine caused reversible voltage-dependent rectification of cloned HRK1 channels. Model: Xenopus oocyte inside-out patches; construct species unresolved in accessed abstract. Limitations: Do not relabel the channel as a verified human isoform or infer a serum-potassium effect. Evidence access: Primary abstract The mechanism of inward rectification of potassium channels: "long-pore plugging" by cytoplasmic polyamines. · 1995 · https://pubmed.ncbi.nlm.nih.gov/8648298/ · DOI 10.1085/jgp.106.5.923

evidence_access

Primary full text

experimental_model

Mouse AML12 cells; 100 micromolar spermidine with palmitate/oleate for 48 hours.

limitations

This concentration is experimental, not a human dosing target.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A lipid-stressed liver-cell model recovered part of its machinery.

primary_references

Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36057633/ · DOI 10.1038/s41467-022-32788-x

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse AML12 cells; 100 micromolar spermidine with palmitate/oleate for 48 hours. · source_derived_draft · unverified_draft

## spermidine-liver-respiration A lipid-stressed liver-cell model recovered part of its machinery. Spermidine partially restored protein synthesis and mitochondrial respiration in fatty-acid-treated AML12 cells. Model: Mouse AML12 cells; 100 micromolar spermidine with palmitate/oleate for 48 hours. Limitations: This concentration is experimental, not a human dosing target. Evidence access: Primary full text Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36057633/ · DOI 10.1038/s41467-022-32788-x

evidence_access

Primary abstract

experimental_model

Mouse exposure and hippocampal measurements.

limitations

Do not infer the same human brain exposure from a plasma measurement.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Brain delivery was tested in mice.

primary_references

Dietary spermidine improves cognitive function. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33852843/ · DOI 10.1016/j.celrep.2021.108985

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse exposure and hippocampal measurements. · source_derived_draft · unverified_draft

## spermidine-mouse-brain-entry Brain delivery was tested in mice. The mouse study reported brain entry of dietary spermidine and increased hippocampal eIF5A hypusination. Model: Mouse exposure and hippocampal measurements. Limitations: Do not infer the same human brain exposure from a plasma measurement. Evidence access: Primary abstract Dietary spermidine improves cognitive function. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33852843/ · DOI 10.1016/j.celrep.2021.108985

evidence_access

Primary abstract

experimental_model

Cultured human cells.

limitations

Does not establish direct binding of spermidine to mTORC1 or a universal rapamycin-like effect.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A nutrient-sensing signal changed alongside recycling.

primary_references

Spermidine induces autophagy by inhibiting the acetyltransferase EP300. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25526088/ · DOI 10.1038/cdd.2014.215

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cultured human cells. · source_derived_draft · unverified_draft

## spermidine-mtorc1 A nutrient-sensing signal changed alongside recycling. Spermidine-associated autophagy induction coincided with inhibition of mTORC1 signaling in the human-cell study. Model: Cultured human cells. Limitations: Does not establish direct binding of spermidine to mTORC1 or a universal rapamycin-like effect. Evidence access: Primary abstract Spermidine induces autophagy by inhibiting the acetyltransferase EP300. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25526088/ · DOI 10.1038/cdd.2014.215

evidence_access

Primary full text

experimental_model

Mouse injury and satellite-cell models.

limitations

Not evidence of human muscle growth or sports-performance enhancement.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

The pathway also participates in repair outside the brain and immune system.

primary_references

Spermidine-eIF5A axis is essential for muscle stem cell activation via translational control. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39251577/ · DOI 10.1038/s41421-024-00712-w

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 374–380

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse injury and satellite-cell models. · source_derived_draft · unverified_draft

## spermidine-muscle-activation The pathway also participates in repair outside the brain and immune system. Spermidine promoted muscle satellite-cell activation and regeneration in mice. Model: Mouse injury and satellite-cell models. Limitations: Not evidence of human muscle growth or sports-performance enhancement. Evidence access: Primary full text Spermidine-eIF5A axis is essential for muscle stem cell activation via translational control. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39251577/ · DOI 10.1038/s41421-024-00712-w

evidence_access

Primary full text

experimental_model

Human PC3/DU145 cells and hypusination perturbation.

limitations

Assay-specific pathway interpretation; does not mean NRF2 is always protective.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A translation response can raise a stress regulator.

primary_references

Spermidine inactivates proteasome activity and enhances ferroptosis in prostate cancer. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40486852/ · DOI 10.1016/j.apsb.2025.02.023

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 510–516

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human PC3/DU145 cells and hypusination perturbation. · source_derived_draft · unverified_draft

## spermidine-nrf2-translation A translation response can raise a stress regulator. The prostate-cell study linked spermidine-driven eIF5A hypusination to increased NRF2 translation. Model: Human PC3/DU145 cells and hypusination perturbation. Limitations: Assay-specific pathway interpretation; does not mean NRF2 is always protective. Evidence access: Primary full text Spermidine inactivates proteasome activity and enhances ferroptosis in prostate cancer. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40486852/ · DOI 10.1016/j.apsb.2025.02.023

evidence_access

Primary full text

experimental_model

Human-cell proteasome activity and protein-stability assays.

limitations

Not proof that spermidine directly binds a specific proteasome subunit.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Protein accumulation can involve slower removal as well as faster production.

primary_references

Spermidine inactivates proteasome activity and enhances ferroptosis in prostate cancer. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40486852/ · DOI 10.1016/j.apsb.2025.02.023

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 518–524

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human-cell proteasome activity and protein-stability assays. · source_derived_draft · unverified_draft

## spermidine-proteasome Protein accumulation can involve slower removal as well as faster production. Spermidine/erastin treatment reduced proteasome activity and NRF2 degradation in the reported prostate-cell experiments. Model: Human-cell proteasome activity and protein-stability assays. Limitations: Not proof that spermidine directly binds a specific proteasome subunit. Evidence access: Primary full text Spermidine inactivates proteasome activity and enhances ferroptosis in prostate cancer. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40486852/ · DOI 10.1016/j.apsb.2025.02.023

evidence_access

Primary abstract

experimental_model

Hypertension/heart-failure rat model.

limitations

Not a demonstrated direct kinase target; blood-pressure reduction may contribute.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A structural heart protein changed alongside cardiac function.

primary_references

Cardioprotection and lifespan extension by the natural polyamine spermidine. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27841876/ · DOI 10.1038/nm.4222

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 342–348

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Hypertension/heart-failure rat model. · source_derived_draft · unverified_draft

## spermidine-rat-titin A structural heart protein changed alongside cardiac function. Spermidine increased titin phosphorylation in high-salt-fed Dahl salt-sensitive rats. Model: Hypertension/heart-failure rat model. Limitations: Not a demonstrated direct kinase target; blood-pressure reduction may contribute. Evidence access: Primary abstract Cardioprotection and lifespan extension by the natural polyamine spermidine. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27841876/ · DOI 10.1038/nm.4222

evidence_access

Primary full text

experimental_model

Serum comparisons and cultured cancer cells.

limitations

Do not mistake serum-generated oxidants for direct intracellular target engagement.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

The culture medium can transform the compound before cells respond.

primary_references

Oxidative degradation of polyamines by serum supplement causes cytotoxicity on cultured cells. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29991686/ · DOI 10.1038/s41598-018-28648-8

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 486–492

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Serum comparisons and cultured cancer cells. · source_derived_draft · unverified_draft

## spermidine-serum-peroxide The culture medium can transform the compound before cells respond. Added spermidine generated hydrogen peroxide in several animal-serum-containing media but not the tested human-serum medium. Model: Serum comparisons and cultured cancer cells. Limitations: Do not mistake serum-generated oxidants for direct intracellular target engagement. Evidence access: Primary full text Oxidative degradation of polyamines by serum supplement causes cytotoxicity on cultured cells. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29991686/ · DOI 10.1038/s41598-018-28648-8

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Anti-CD3/CD28-stimulated donor cells; 10 micromolar spermidine.

limitations

Ex-vivo treatment does not establish an effective oral dose.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

The recycling response was recoverable in cultured T cells.

primary_references

Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33317695/ · DOI 10.7554/eLife.57950

trigger_kind

biomarker_context Imported condition classification; unverified.

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 238–244

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Anti-CD3/CD28-stimulated donor cells; 10 micromolar spermidine. · source_derived_draft · unverified_draft

## spermidine-tcell-autophagy The recycling response was recoverable in cultured T cells. Adding spermidine restored autophagic flux in stimulated T cells from older human donors. Model: Anti-CD3/CD28-stimulated donor cells; 10 micromolar spermidine. Limitations: Ex-vivo treatment does not establish an effective oral dose. Evidence access: Primary full text Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33317695/ · DOI 10.7554/eLife.57950

evidence_access

Primary full text

experimental_model

Primary human cells; cytokine and effector-protein assays.

limitations

The vaccine cohort provided associations; subjects were not randomized to oral spermidine for vaccine enhancement.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Functional measurements accompanied the recycling markers.

primary_references

Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33317695/ · DOI 10.7554/eLife.57950

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 254–260

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary human cells; cytokine and effector-protein assays. · source_derived_draft · unverified_draft

## spermidine-tcell-function Functional measurements accompanied the recycling markers. Spermidine improved effector-function readouts in cultured T cells from older donors. Model: Primary human cells; cytokine and effector-protein assays. Limitations: The vaccine cohort provided associations; subjects were not randomized to oral spermidine for vaccine enhancement. Evidence access: Primary full text Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33317695/ · DOI 10.7554/eLife.57950

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Primary human T-cell cultures.

limitations

Total eIF5A and its modified fraction are different measurements.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A measured protein response links the pathway to autophagy.

primary_references

Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33317695/ · DOI 10.7554/eLife.57950

trigger_kind

biomarker_context Imported condition classification; unverified.

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 246–252

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary human T-cell cultures. · source_derived_draft · unverified_draft

## spermidine-tcell-tfeb A measured protein response links the pathway to autophagy. Spermidine restored TFEB protein and eIF5A hypusination in older-donor CD8 cells and in DFMO-treated young-donor cells. Model: Primary human T-cell cultures. Limitations: Total eIF5A and its modified fraction are different measurements. Evidence access: Primary full text Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33317695/ · DOI 10.7554/eLife.57950

access_level

full_text_and_supplement_review

compartment

Cardiac tissue / mitochondria

dose

30 mM drinking water, as reported

duration

10 weeks in Results

endpoint

mouse-cardiac-fao

evidence_location

Figure 8C–E

experimental_model

Mouse two-hit HFpEF model: 60% fat-calorie diet plus L-NAME 0.5 g/L drinking water; additional intervention as stated

exposure

spermidine

limitations

Single primary study; not independently replicated here. Cardiac and recombinant findings do not establish pulmonary endothelial, viral-sepsis or ARDS effects. Mouse model; no human dose or efficacy inference. Treatment duration differs from the general 15-week model description.

nutrient_topic

Topical cross-reference only; no inheritance of another actor's effects. · Spermidine

organism

Mus musculus

plain_language

Spermidine-treated HFpEF mice showed improved fatty-acid-supported cardiac respiration.

primary_locator

[{"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 54, "text_sha256": "ecfe210aa0338ec52935a354f2bcc46289d65981b7b09fd4299e4e4f2fac4254", "xml_element_id": "Par22"}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 56, "text_sha256": "b4baf8321f41630eff2d66a4181f2907f674041d430ba7878fd278f33d4141cf", "xml_element_id": null}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 72, "text_sha256": "2b1ada63fe6c48d4296bbfb14a97940ac4a866b1d5171b0923851ec72f88ab15", "xml_element_id": "Par31"}]

primary_references

https://doi.org/10.1038/s41467-026-70703-w

route

Drinking water

sample_size

4 biological replicates

tissue_or_cell_type

Cardiac tissue and cardiomyocytes

DLAT: cardiac fatty-acid oxidation and mitochondrial glutathione evidence · lines 660–676

AI-assisted two-paper curation, 2026-09-20. Cardiac full-text/supplement review; CRC abstract only. No pulmonary endothelial validation. · supports · Mouse two-hit HFpEF model: 60% fat-calorie diet plus L-NAME 0.5 g/L drinking water; additional intervention as stated · source_derived_draft · unverified_draft

Spermidine-treated HFpEF mice showed improved fatty-acid-supported cardiac respiration. organism: Mus musculus tissue_or_cell_type: Cardiac tissue and cardiomyocytes experimental_model: Mouse two-hit HFpEF model: 60% fat-calorie diet plus L-NAME 0.5 g/L drinking water; additional intervention as stated compartment: Cardiac tissue / mitochondria dose: 30 mM drinking water, as reported duration: 10 weeks in Results route: Drinking water primary_references: https://doi.org/10.1038/s41467-026-70703-w access_level: full_text_and_supplement_review evidence_location: Figure 8C–E endpoint: mouse-cardiac-fao exposure: spermidine limitations: Single primary study; not independently replicated here. Cardiac and recombinant findings do not establish pulmonary endothelial, viral-sepsis or ARDS effects. Mouse model; no human dose or efficacy inference. Treatment duration differs from the general 15-week model description. primary_locator: [{"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 54, "text_sha256": "ecfe210aa0338ec52935a354f2bcc46289d65981b7b09fd4299e4e4f2fac4254", "xml_element_id": "Par22"}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 56, "text_sha256": "b4baf8321f41630eff2d66a4181f2907f674041d430ba7878fd278f33d4141cf", "xml_element_id": null}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 72, "text_sha256": "2b1ada63fe6c48d4296bbfb14a97940ac4a866b1d5171b0923851ec72f88ab15", "xml_element_id": "Par31"}] plain_language: Spermidine-treated HFpEF mice showed improved fatty-acid-supported cardiac respiration. sample_size: 4 biological replicates

access_level

full_text_and_supplement_review

compartment

Cardiac tissue / mitochondria

dose

30 mM drinking water

duration

10 weeks in Results

endpoint

mouse-cardiac-diastolic-impairment

evidence_location

Figure 8H–K; Supplementary Figure S24

experimental_model

Mouse two-hit HFpEF model: 60% fat-calorie diet plus L-NAME 0.5 g/L drinking water; additional intervention as stated

exposure

spermidine

limitations

Single primary study; not independently replicated here. Cardiac and recombinant findings do not establish pulmonary endothelial, viral-sepsis or ARDS effects. HADHA necessity for this systemic intervention was not established by a genetic blocking experiment.

nutrient_topic

Topical cross-reference only; no inheritance of another actor's effects. · Spermidine

organism

Mus musculus

plain_language

Spermidine improved the reported diastolic phenotype of mice in the HFpEF experiment.

primary_locator

[{"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 54, "text_sha256": "ecfe210aa0338ec52935a354f2bcc46289d65981b7b09fd4299e4e4f2fac4254", "xml_element_id": "Par22"}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 56, "text_sha256": "b4baf8321f41630eff2d66a4181f2907f674041d430ba7878fd278f33d4141cf", "xml_element_id": null}]

primary_references

https://doi.org/10.1038/s41467-026-70703-w

route

Drinking water

sample_size

8 per group

tissue_or_cell_type

Cardiac tissue and cardiomyocytes

DLAT: cardiac fatty-acid oxidation and mitochondrial glutathione evidence · lines 679–695

AI-assisted two-paper curation, 2026-09-20. Cardiac full-text/supplement review; CRC abstract only. No pulmonary endothelial validation. · supports · Mouse two-hit HFpEF model: 60% fat-calorie diet plus L-NAME 0.5 g/L drinking water; additional intervention as stated · source_derived_draft · unverified_draft

Spermidine improved the reported diastolic phenotype of mice in the HFpEF experiment. organism: Mus musculus tissue_or_cell_type: Cardiac tissue and cardiomyocytes experimental_model: Mouse two-hit HFpEF model: 60% fat-calorie diet plus L-NAME 0.5 g/L drinking water; additional intervention as stated compartment: Cardiac tissue / mitochondria dose: 30 mM drinking water duration: 10 weeks in Results route: Drinking water primary_references: https://doi.org/10.1038/s41467-026-70703-w access_level: full_text_and_supplement_review evidence_location: Figure 8H–K; Supplementary Figure S24 endpoint: mouse-cardiac-diastolic-impairment exposure: spermidine limitations: Single primary study; not independently replicated here. Cardiac and recombinant findings do not establish pulmonary endothelial, viral-sepsis or ARDS effects. HADHA necessity for this systemic intervention was not established by a genetic blocking experiment. primary_locator: [{"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 54, "text_sha256": "ecfe210aa0338ec52935a354f2bcc46289d65981b7b09fd4299e4e4f2fac4254", "xml_element_id": "Par22"}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 56, "text_sha256": "b4baf8321f41630eff2d66a4181f2907f674041d430ba7878fd278f33d4141cf", "xml_element_id": null}] plain_language: Spermidine improved the reported diastolic phenotype of mice in the HFpEF experiment. sample_size: 8 per group

access_level

full_text_and_supplement_review

compartment

Cardiac tissue / mitochondria

dose

30 mM in drinking water, as reported

duration

10 weeks in the Results; broader two-hit methods specify 15 weeks

endpoint

hadha-attributed-lysate-activity

evidence_location

Figure 8A/B

experimental_model

Mouse two-hit HFpEF model: 60% fat-calorie diet plus L-NAME 0.5 g/L drinking water; additional intervention as stated

exposure

spermidine

limitations

Single primary study; not independently replicated here. Cardiac and recombinant findings do not establish pulmonary endothelial, viral-sepsis or ARDS effects. This paper does not itself establish direct spermidine binding; that statement cites earlier work. Do not infer intake in mg/kg from water concentration. Lysate specificity/protocol units remain qualified.

nutrient_topic

Topical cross-reference only; no inheritance of another actor's effects. · Spermidine

organism

Mus musculus

plain_language

Spermidine increased the HADHA-attributed activity readout in mouse cardiac lysates from treated animals.

primary_locator

[{"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 54, "text_sha256": "ecfe210aa0338ec52935a354f2bcc46289d65981b7b09fd4299e4e4f2fac4254", "xml_element_id": "Par22"}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 56, "text_sha256": "b4baf8321f41630eff2d66a4181f2907f674041d430ba7878fd278f33d4141cf", "xml_element_id": null}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 72, "text_sha256": "2b1ada63fe6c48d4296bbfb14a97940ac4a866b1d5171b0923851ec72f88ab15", "xml_element_id": "Par31"}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 102, "text_sha256": "299ae9af6e500af03d85d3cc327c60cb04e94f0618b6a9910780ac928e42faff", "xml_element_id": "Par46"}]

primary_references

https://doi.org/10.1038/s41467-026-70703-w

route

Drinking water

sample_size

4 per group

tissue_or_cell_type

Cardiac tissue and cardiomyocytes

DLAT: cardiac fatty-acid oxidation and mitochondrial glutathione evidence · lines 641–657

AI-assisted two-paper curation, 2026-09-20. Cardiac full-text/supplement review; CRC abstract only. No pulmonary endothelial validation. · supports · Mouse two-hit HFpEF model: 60% fat-calorie diet plus L-NAME 0.5 g/L drinking water; additional intervention as stated · source_derived_draft · unverified_draft

Spermidine increased the HADHA-attributed activity readout in mouse cardiac lysates from treated animals. organism: Mus musculus tissue_or_cell_type: Cardiac tissue and cardiomyocytes experimental_model: Mouse two-hit HFpEF model: 60% fat-calorie diet plus L-NAME 0.5 g/L drinking water; additional intervention as stated compartment: Cardiac tissue / mitochondria dose: 30 mM in drinking water, as reported duration: 10 weeks in the Results; broader two-hit methods specify 15 weeks route: Drinking water primary_references: https://doi.org/10.1038/s41467-026-70703-w access_level: full_text_and_supplement_review evidence_location: Figure 8A/B endpoint: hadha-attributed-lysate-activity exposure: spermidine limitations: Single primary study; not independently replicated here. Cardiac and recombinant findings do not establish pulmonary endothelial, viral-sepsis or ARDS effects. This paper does not itself establish direct spermidine binding; that statement cites earlier work. Do not infer intake in mg/kg from water concentration. Lysate specificity/protocol units remain qualified. primary_locator: [{"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 54, "text_sha256": "ecfe210aa0338ec52935a354f2bcc46289d65981b7b09fd4299e4e4f2fac4254", "xml_element_id": "Par22"}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 56, "text_sha256": "b4baf8321f41630eff2d66a4181f2907f674041d430ba7878fd278f33d4141cf", "xml_element_id": null}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 72, "text_sha256": "2b1ada63fe6c48d4296bbfb14a97940ac4a866b1d5171b0923851ec72f88ab15", "xml_element_id": "Par31"}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 102, "text_sha256": "299ae9af6e500af03d85d3cc327c60cb04e94f0618b6a9910780ac928e42faff", "xml_element_id": "Par46"}] plain_language: Spermidine increased the HADHA-attributed activity readout in mouse cardiac lysates from treated animals. sample_size: 4 per group

evidence_access

Primary abstract

experimental_model

Human SMS structures and catalytic assays.

limitations

A pathway connection does not mean arginine is always rate limiting.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

The polyamine pathway extends beyond spermidine.

primary_references

Crystal structure of human spermine synthase: implications of substrate binding and catalytic mechanism. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18367445/ · DOI 10.1074/jbc.m710323200

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 158–164

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human SMS structures and catalytic assays. · source_derived_draft · unverified_draft

## arg-sms The polyamine pathway extends beyond spermidine. Human spermine-synthase substrate/product structures and mutagenesis support aminopropyl transfer to spermidine. Model: Human SMS structures and catalytic assays. Limitations: A pathway connection does not mean arginine is always rate limiting. Evidence access: Primary abstract Crystal structure of human spermine synthase: implications of substrate binding and catalytic mechanism. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18367445/ · DOI 10.1074/jbc.m710323200

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human pancreatic cancer lines and radiolabeled uptake assays.

limitations

Cancer-cell uptake is not proof of human intestinal absorption; impairment is explicit.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Cellular uptake depends on a distinct transport protein.

primary_references

ATP13A3 facilitates polyamine transport in human pancreatic cancer cells. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35260637/ · DOI 10.1038/s41598-022-07712-4

trigger_kind

machinery_impairment Imported condition classification; unverified.

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 134–140

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human pancreatic cancer lines and radiolabeled uptake assays. · source_derived_draft · unverified_draft

## spermidine-atp13a3-uptake Cellular uptake depends on a distinct transport protein. CRISPR disruption of the first membrane-associated region of ATP13A3 impaired spermidine transport in human pancreatic cancer cells. Model: Human pancreatic cancer lines and radiolabeled uptake assays. Limitations: Cancer-cell uptake is not proof of human intestinal absorption; impairment is explicit. Evidence access: Primary full text ATP13A3 facilitates polyamine transport in human pancreatic cancer cells. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35260637/ · DOI 10.1038/s41598-022-07712-4

evidence_access

Primary abstract

experimental_model

Human enzyme, NAD, labeled protein and diamine substrate.

limitations

No in-vivo flux or dominant recycling contribution established.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

An unfinished protein modification can be reversed in vitro.

primary_references

Reversal of the deoxyhypusine synthesis reaction. Generation of spermidine or homospermidine from deoxyhypusine by deoxyhypusine synthase. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12788913/ · DOI 10.1074/jbc.M304247200

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 38–44

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme, NAD, labeled protein and diamine substrate. · source_derived_draft · unverified_draft

## spermidine-dhps-reversal An unfinished protein modification can be reversed in vitro. Purified human DHPS transferred radiolabeled aminobutyl from deoxyhypusine-eIF5A to 1,3-diaminopropane, regenerating spermidine. Model: Human enzyme, NAD, labeled protein and diamine substrate. Limitations: No in-vivo flux or dominant recycling contribution established. Evidence access: Primary abstract Reversal of the deoxyhypusine synthesis reaction. Generation of spermidine or homospermidine from deoxyhypusine by deoxyhypusine synthase. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12788913/ · DOI 10.1074/jbc.M304247200

evidence_access

Primary abstract

experimental_model

HRK1 patch-clamp comparison.

limitations

This is a gating comparison, not evidence that one nutrient replaces the other.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Magnesium and spermidine influence the same channel with different kinetics.

primary_references

The mechanism of inward rectification of potassium channels: "long-pore plugging" by cytoplasmic polyamines. · 1995 · https://pubmed.ncbi.nlm.nih.gov/8648298/ · DOI 10.1085/jgp.106.5.923

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 438–444

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · HRK1 patch-clamp comparison. · source_derived_draft · unverified_draft

## spermidine-kir-magnesium Magnesium and spermidine influence the same channel with different kinetics. Magnesium-associated unblock was almost instantaneous, whereas spermidine unblock was time dependent. Model: HRK1 patch-clamp comparison. Limitations: This is a gating comparison, not evidence that one nutrient replaces the other. Evidence access: Primary abstract The mechanism of inward rectification of potassium channels: "long-pore plugging" by cytoplasmic polyamines. · 1995 · https://pubmed.ncbi.nlm.nih.gov/8648298/ · DOI 10.1085/jgp.106.5.923

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Bacterial gene deletion and polyamine analysis.

limitations

The paper’s microbiome-wide prevalence claim is based on genomic inference; not measured production in each human.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Bacteria can use a route different from the human SAM pathway.

primary_references

Alternative spermidine biosynthetic route is critical for growth of Campylobacter jejuni and is the dominant polyamine pathway in human gut microbiota. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22025614/ · DOI 10.1074/jbc.M111.307835

trigger_kind

machinery_impairment Imported condition classification; unverified.

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 414–420

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Bacterial gene deletion and polyamine analysis. · source_derived_draft · unverified_draft

## spermidine-microbial-route Bacteria can use a route different from the human SAM pathway. Deleting the carboxypolyamine-decarboxylase orthologue disrupted spermidine synthesis in Campylobacter jejuni. Model: Bacterial gene deletion and polyamine analysis. Limitations: The paper’s microbiome-wide prevalence claim is based on genomic inference; not measured production in each human. Evidence access: Primary abstract Alternative spermidine biosynthetic route is critical for growth of Campylobacter jejuni and is the dominant polyamine pathway in human gut microbiota. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22025614/ · DOI 10.1074/jbc.M111.307835

evidence_access

Primary abstract

experimental_model

Receptors expressed in Xenopus oocytes and HEK293 cells; isotonic extracellular solutions.

limitations

Millimolar experimental kinetics are not physiological brain concentrations.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A receptor channel can also provide an entry route.

primary_references

Spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg(2+). · 2015 · https://pubmed.ncbi.nlm.nih.gov/26086092/ · DOI 10.1016/j.bbrc.2015.06.081

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 446–452

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Receptors expressed in Xenopus oocytes and HEK293 cells; isotonic extracellular solutions. · source_derived_draft · unverified_draft

## spermidine-nmda-entry A receptor channel can also provide an entry route. Spermidine permeated activated GluN1/GluN2A and GluN1/GluN2B channels; reported Km values were 2.2 and 2.7 mM. Model: Receptors expressed in Xenopus oocytes and HEK293 cells; isotonic extracellular solutions. Limitations: Millimolar experimental kinetics are not physiological brain concentrations. Evidence access: Primary abstract Spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg(2+). · 2015 · https://pubmed.ncbi.nlm.nih.gov/26086092/ · DOI 10.1016/j.bbrc.2015.06.081

evidence_access

Primary abstract

experimental_model

Purified recombinant human SAT1 kinetics and structural analysis.

limitations

Acetyl-CoA dependence connects to CoA metabolism, not demonstrated pantothenate depletion.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A CoA-dependent step changes how spermidine is recycled.

primary_references

Mechanistic and structural analysis of human spermidine/spermine N1-acetyltransferase. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17516632/ · DOI 10.1021/bi700256z

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 78–84

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified recombinant human SAT1 kinetics and structural analysis. · source_derived_draft · unverified_draft

## spermidine-sat1-substrate A CoA-dependent step changes how spermidine is recycled. Human SAT1 catalyzes N1-acetylation of spermidine using acetyl-CoA. Model: Purified recombinant human SAT1 kinetics and structural analysis. Limitations: Acetyl-CoA dependence connects to CoA metabolism, not demonstrated pantothenate depletion. Evidence access: Primary abstract Mechanistic and structural analysis of human spermidine/spermine N1-acetyltransferase. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17516632/ · DOI 10.1021/bi700256z

evidence_access

Primary full text

experimental_model

Reconstituted purified human transporter.

limitations

Not a measurement of brain exposure after an oral supplement.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Vesicles use a proton gradient to store polyamines.

primary_references

Identification of a mammalian vesicular polyamine transporter. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25355561/ · DOI 10.1038/srep06836

transport_effect

raises Recorded as transport of spermidine into proteoliposomes by proton exchange.

transport_pool

the secretory-vesicle lumen Recorded as transport of spermidine into proteoliposomes by proton exchange.

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 142–148

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Reconstituted purified human transporter. · source_derived_draft · unverified_draft

## spermidine-vesicle-transport Vesicles use a proton gradient to store polyamines. Purified human SLC18B1 transported spermidine into proteoliposomes by proton exchange. Model: Reconstituted purified human transporter. Limitations: Not a measurement of brain exposure after an oral supplement. Evidence access: Primary full text Identification of a mammalian vesicular polyamine transporter. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25355561/ · DOI 10.1038/srep06836

evidence_access

Primary abstract

experimental_model

Human enzyme structural, biochemical and mutagenesis experiments.

limitations

This consumes an aminopropyl donor, not a direct methyl transfer from ordinary SAM.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Polyamine synthesis combines an ornithine-derived branch with a SAM-derived branch.

primary_references

Structure and mechanism of spermidine synthases. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17585781/ · DOI 10.1021/bi602498k

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 134–140

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme structural, biochemical and mutagenesis experiments. · source_derived_draft · unverified_draft

## arg-srm Polyamine synthesis combines an ornithine-derived branch with a SAM-derived branch. Human SRM uses putrescine as the amine acceptor for aminopropyl transfer from decarboxylated SAM. Model: Human enzyme structural, biochemical and mutagenesis experiments. Limitations: This consumes an aminopropyl donor, not a direct methyl transfer from ordinary SAM. Evidence access: Primary abstract Structure and mechanism of spermidine synthases. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17585781/ · DOI 10.1021/bi602498k

evidence_access

Primary abstract

experimental_model

Cell and translation assays; exact construct and cell species not resolved in accessed abstract.

limitations

This is not assigned to a human isoform without checking the complete preparation.

nutrient_topic

Agmatine Sulfate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Agmatine Sulfate

plain_language

It can influence production of a regulator of polyamine metabolism.

primary_references

Agmatine suppresses proliferation by frameshift induction of antizyme and attenuation of cellular polyamine levels. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9624108/ · DOI 10.1074/jbc.273.25.15313

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 340–346

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cell and translation assays; exact construct and cell species not resolved in accessed abstract. · source_derived_draft · unverified_draft

## agmatine-sulfate-antizyme-frameshift It can influence production of a regulator of polyamine metabolism. Agmatine promoted an antizyme-mRNA frameshift producing full-length antizyme; anti-antizyme antibody or antizyme inhibitor suppressed associated inhibitory activity. Model: Cell and translation assays; exact construct and cell species not resolved in accessed abstract. Limitations: This is not assigned to a human isoform without checking the complete preparation. Evidence access: Primary abstract Agmatine suppresses proliferation by frameshift induction of antizyme and attenuation of cellular polyamine levels. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9624108/ · DOI 10.1074/jbc.273.25.15313

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Pharmacological ODC inhibition in rat hepatocyte culture.

limitations

This is experimentally induced cellular polyamine depletion, not ordinary dietary agmatine deficiency.

nutrient_topic

Agmatine Sulfate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Agmatine Sulfate

plain_language

A depleted downstream pool can change entry of another compound.

primary_references

Transport and metabolism of agmatine in rat hepatocyte cultures. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11179960/ · DOI 10.1046/j.1432-1327.2001.01955.x

trigger_kind

machinery_impairment Imported condition classification; unverified.

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 84–90

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Pharmacological ODC inhibition in rat hepatocyte culture. · source_derived_draft · unverified_draft

## agmatine-sulfate-depleted-polyamines A depleted downstream pool can change entry of another compound. Difluoromethylornithine-induced polyamine depletion increased agmatine uptake in cultured rat hepatocytes. Model: Pharmacological ODC inhibition in rat hepatocyte culture. Limitations: This is experimentally induced cellular polyamine depletion, not ordinary dietary agmatine deficiency. Evidence access: Primary abstract Transport and metabolism of agmatine in rat hepatocyte cultures. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11179960/ · DOI 10.1046/j.1432-1327.2001.01955.x

evidence_access

Primary abstract

experimental_model

Mouse transformed fibroblast transport experiments.

limitations

The molecular transporter gene was not identified; this system is not automatically OCT2 or MATE1.

nutrient_topic

Agmatine Sulfate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Agmatine Sulfate

plain_language

Different cells can have much higher-affinity uptake than a single recombinant transporter.

primary_references

Polyamine transport system mediates agmatine transport in mammalian cells. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11401856/ · DOI 10.1152/ajpcell.2001.281.1.C329

transport_effect

raises Cells took up agmatine through an energy- and membrane-potential-dependent saturable system.

transport_pool

the expressing cell Cells took up agmatine through an energy- and membrane-potential-dependent saturable system.

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 60–66

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse transformed fibroblast transport experiments. · source_derived_draft · unverified_draft

## agmatine-sulfate-polyamine-carrier Different cells can have much higher-affinity uptake than a single recombinant transporter. Transformed mouse NIH/3T3 cells took up agmatine through an energy- and membrane-potential-dependent saturable system with apparent Km 2.5 micromolar. Model: Mouse transformed fibroblast transport experiments. Limitations: The molecular transporter gene was not identified; this system is not automatically OCT2 or MATE1. Evidence access: Primary abstract Polyamine transport system mediates agmatine transport in mammalian cells. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11401856/ · DOI 10.1152/ajpcell.2001.281.1.C329

evidence_access

Primary abstract

experimental_model

Primary rat hepatocyte cultures and radiolabeled substrate.

limitations

Different selectivity from other polyamine uptake systems is a context difference, not a universal contradiction.

nutrient_topic

Agmatine Sulfate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Agmatine Sulfate

plain_language

Competition depends on which cell and transport route is being studied.

primary_references

Transport and metabolism of agmatine in rat hepatocyte cultures. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11179960/ · DOI 10.1046/j.1432-1327.2001.01955.x

transport_effect

raises Hepatocytes showed high-affinity agmatine uptake with a Km of 0.03 mM.

transport_pool

the hepatocyte interior Hepatocytes showed high-affinity agmatine uptake with a Km of 0.03 mM.

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 76–82

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary rat hepatocyte cultures and radiolabeled substrate. · source_derived_draft · unverified_draft

## agmatine-sulfate-rat-liver-uptake Competition depends on which cell and transport route is being studied. Rat hepatocytes exhibited high-affinity agmatine uptake with Km 0.03 mM; the system also transported putrescine but not arginine, spermidine or spermine. Model: Primary rat hepatocyte cultures and radiolabeled substrate. Limitations: Different selectivity from other polyamine uptake systems is a context difference, not a universal contradiction. Evidence access: Primary abstract Transport and metabolism of agmatine in rat hepatocyte cultures. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11179960/ · DOI 10.1046/j.1432-1327.2001.01955.x

evidence_access

Primary abstract

experimental_model

Rat pulmonary endothelial transport kinetics.

limitations

No universal human polyamine depletion magnitude or clinical supplement interaction is established.

nutrient_topic

Agmatine Sulfate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Agmatine Sulfate

plain_language

Immediate transport competition can coexist with slower regulation of protein expression.

primary_references

Regulation of ornithine decarboxylase activity and polyamine transport by agmatine in rat pulmonary artery endothelial cells. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11160620/

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 364–370

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat pulmonary endothelial transport kinetics. · source_derived_draft · unverified_draft

## agmatine-sulfate-rat-polyamine-competition Immediate transport competition can coexist with slower regulation of protein expression. Agmatine present in culture medium competitively inhibited radiolabeled polyamine uptake, increasing apparent Km. Model: Rat pulmonary endothelial transport kinetics. Limitations: No universal human polyamine depletion magnitude or clinical supplement interaction is established. Evidence access: Primary abstract Regulation of ornithine decarboxylase activity and polyamine transport by agmatine in rat pulmonary artery endothelial cells. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11160620/

evidence_access

Primary abstract

experimental_model

Primary rat hepatocytes with radiotracer.

limitations

The abstract reports a polyamine pool, not a putrescine-only percentage or purified human AGMAT reaction.

nutrient_topic

Agmatine Sulfate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Agmatine Sulfate

plain_language

Agmatine can feed polyamine metabolism in a defined preparation.

primary_references

Transport and metabolism of agmatine in rat hepatocyte cultures. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11179960/ · DOI 10.1046/j.1432-1327.2001.01955.x

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 100–106

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary rat hepatocytes with radiotracer. · source_derived_draft · unverified_draft

## agmatine-sulfate-rat-polyamine-production Agmatine can feed polyamine metabolism in a defined preparation. About 10% of taken-up agmatine label entered the polyamine pool in rat hepatocyte cultures. Model: Primary rat hepatocytes with radiotracer. Limitations: The abstract reports a polyamine pool, not a putrescine-only percentage or purified human AGMAT reaction. Evidence access: Primary abstract Transport and metabolism of agmatine in rat hepatocyte cultures. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11179960/ · DOI 10.1046/j.1432-1327.2001.01955.x

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse macrophage in-vitro and in-vivo models.

limitations

Alternative activation is not universally beneficial or equivalent to lower inflammation in every disease.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

The same pathway affects immune states differently.

primary_references

Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31130465/ · DOI 10.1016/j.cmet.2019.05.003

trigger_kind

machinery_impairment Imported condition classification; unverified.

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 294–300

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse macrophage in-vitro and in-vivo models. · source_derived_draft · unverified_draft

## spermidine-alternative-macrophage The same pathway affects immune states differently. Acute inhibition of hypusination impaired alternative macrophage activation while largely sparing glycolysis-associated classical activation. Model: Mouse macrophage in-vitro and in-vivo models. Limitations: Alternative activation is not universally beneficial or equivalent to lower inflammation in every disease. Evidence access: Primary full text Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31130465/ · DOI 10.1016/j.cmet.2019.05.003

evidence_access

Primary abstract

experimental_model

Purified human transporter and cellular transport experiments.

limitations

Polyamine-class result; strongest affinity was for spermine, not necessarily spermidine.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A molecule can enter a cell yet remain trapped in a compartment.

primary_references

ATP13A2 deficiency disrupts lysosomal polyamine export. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31996848/ · DOI 10.1038/s41586-020-1968-7

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 118–124

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human transporter and cellular transport experiments. · source_derived_draft · unverified_draft

## spermidine-atp13a2-export A molecule can enter a cell yet remain trapped in a compartment. ATP13A2 supports lysosomal polyamine export to cytosol after endocytic uptake; spermine had the highest tested affinity. Model: Purified human transporter and cellular transport experiments. Limitations: Polyamine-class result; strongest affinity was for spermine, not necessarily spermidine. Evidence access: Primary abstract ATP13A2 deficiency disrupts lysosomal polyamine export. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31996848/ · DOI 10.1038/s41586-020-1968-7

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human transporter/cell experiments; neuronal and nematode validation in the paper.

limitations

Do not infer that dietary spermidine treats ATP13A2 disease; high-exposure findings retain their context.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A transport defect can make extra polyamine harmful.

primary_references

ATP13A2 deficiency disrupts lysosomal polyamine export. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31996848/ · DOI 10.1038/s41586-020-1968-7

trigger_kind

machinery_impairment Imported condition classification; unverified.

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 126–132

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human transporter/cell experiments; neuronal and nematode validation in the paper. · source_derived_draft · unverified_draft

## spermidine-atp13a2-failure A transport defect can make extra polyamine harmful. Loss or disease-associated impairment of ATP13A2 reduced export function and worsened high-polyamine lysosomal injury. Model: Human transporter/cell experiments; neuronal and nematode validation in the paper. Limitations: Do not infer that dietary spermidine treats ATP13A2 disease; high-exposure findings retain their context. Evidence access: Primary abstract ATP13A2 deficiency disrupts lysosomal polyamine export. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31996848/ · DOI 10.1038/s41586-020-1968-7

evidence_access

Primary full text

experimental_model

Purified human DHPS crystallography and single-turnover assays.

limitations

NAD is regenerated during the reaction; this does not measure NAD depletion or establish niacin supplementation benefit.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A niacin-derived coenzyme participates in using spermidine.

primary_references

Half Way to Hypusine-Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32235505/ · DOI 10.3390/biom10040522

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 14–20

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human DHPS crystallography and single-turnover assays. · source_derived_draft · unverified_draft

## spermidine-dhps-nad A niacin-derived coenzyme participates in using spermidine. Human DHPS binds NAD and spermidine; NAD-dependent chemistry initiates aminobutyl transfer. Model: Purified human DHPS crystallography and single-turnover assays. Limitations: NAD is regenerated during the reaction; this does not measure NAD depletion or establish niacin supplementation benefit. Evidence access: Primary full text Half Way to Hypusine-Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32235505/ · DOI 10.3390/biom10040522

evidence_access

Primary abstract

experimental_model

Purified recombinant human DOHH; EPR, Mossbauer, XAS and Raman spectroscopy.

limitations

Not a clinical iron-deficiency threshold or evidence that extra iron improves spermidine responses.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Iron is part of the enzyme that completes hypusination.

primary_references

Human deoxyhypusine hydroxylase, an enzyme involved in regulating cell growth, activates O2 with a nonheme diiron center. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19706422/ · DOI 10.1073/pnas.0904553106

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 54–60

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified recombinant human DOHH; EPR, Mossbauer, XAS and Raman spectroscopy. · source_derived_draft · unverified_draft

## spermidine-dohh-iron Iron is part of the enzyme that completes hypusination. Spectroscopy established a coupled diiron center in human DOHH, whose reduced state activates oxygen. Model: Purified recombinant human DOHH; EPR, Mossbauer, XAS and Raman spectroscopy. Limitations: Not a clinical iron-deficiency threshold or evidence that extra iron improves spermidine responses. Evidence access: Primary abstract Human deoxyhypusine hydroxylase, an enzyme involved in regulating cell growth, activates O2 with a nonheme diiron center. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19706422/ · DOI 10.1073/pnas.0904553106

evidence_access

Primary abstract

experimental_model

Human enzyme; 1.7-angstrom structures and spectroscopy.

limitations

DOHH is not a collagen-type 2-oxoglutarate hydroxylase; do not infer the same vitamin C requirement.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Oxygen chemistry completes the protein modification.

primary_references

Crystal Structure of the Peroxo-diiron(III) Intermediate of Deoxyhypusine Hydroxylase, an Oxygenase Involved in Hypusination. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25865244/ · DOI 10.1016/j.str.2015.03.002

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 62–68

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme; 1.7-angstrom structures and spectroscopy. · source_derived_draft · unverified_draft

## spermidine-dohh-oxygen Oxygen chemistry completes the protein modification. Human DOHH structures resolved a peroxo-diiron intermediate involved in hydroxylating deoxyhypusine-eIF5A. Model: Human enzyme; 1.7-angstrom structures and spectroscopy. Limitations: DOHH is not a collagen-type 2-oxoglutarate hydroxylase; do not infer the same vitamin C requirement. Evidence access: Primary abstract Crystal Structure of the Peroxo-diiron(III) Intermediate of Deoxyhypusine Hydroxylase, an Oxygenase Involved in Hypusination. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25865244/ · DOI 10.1016/j.str.2015.03.002

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human-cell RNA interference screen of 43 acetyltransferases.

limitations

Does not prove all spermidine effects are mediated by EP300.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Removing a regulator supports a causal pathway.

primary_references

Spermidine induces autophagy by inhibiting the acetyltransferase EP300. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25526088/ · DOI 10.1038/cdd.2014.215

trigger_kind

machinery_impairment Imported condition classification; unverified.

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 174–180

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human-cell RNA interference screen of 43 acetyltransferases. · source_derived_draft · unverified_draft

## spermidine-ep300-loss Removing a regulator supports a causal pathway. EP300 knockdown induced autophagy and reduced mTORC1 activity in the acetyltransferase screen. Model: Human-cell RNA interference screen of 43 acetyltransferases. Limitations: Does not prove all spermidine effects are mediated by EP300. Evidence access: Primary abstract Spermidine induces autophagy by inhibiting the acetyltransferase EP300. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25526088/ · DOI 10.1038/cdd.2014.215

evidence_access

Primary full text

experimental_model

Healthy human volunteers sampled during fasting.

limitations

Not a causal test of human longevity or a recommendation for prolonged fasting.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Human blood cells showed a pathway response.

primary_references

Spermidine is essential for fasting-mediated autophagy and longevity. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39117797/ · DOI 10.1038/s41556-024-01468-x

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 206–212

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Healthy human volunteers sampled during fasting. · source_derived_draft · unverified_draft

## spermidine-fasting-human Human blood cells showed a pathway response. PBMC hypusinated eIF5A increased during the studied multiday fasting regimen and remained elevated after food reintroduction. Model: Healthy human volunteers sampled during fasting. Limitations: Not a causal test of human longevity or a recommendation for prolonged fasting. Evidence access: Primary full text Spermidine is essential for fasting-mediated autophagy and longevity. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39117797/ · DOI 10.1038/s41556-024-01468-x

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human U2OS cells.

limitations

ODC1 supplies several polyamines; depletion is not spermidine-specific.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Genetic evidence complements the inhibitor experiment.

primary_references

Spermidine is essential for fasting-mediated autophagy and longevity. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39117797/ · DOI 10.1038/s41556-024-01468-x

trigger_kind

machinery_impairment Imported condition classification; unverified.

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 198–204

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human U2OS cells. · source_derived_draft · unverified_draft

## spermidine-fasting-knockdown Genetic evidence complements the inhibitor experiment. Three ODC1-directed siRNAs depleted polyamines and reduced starvation-induced autophagic flux. Model: Human U2OS cells. Limitations: ODC1 supplies several polyamines; depletion is not spermidine-specific. Evidence access: Primary full text Spermidine is essential for fasting-mediated autophagy and longevity. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39117797/ · DOI 10.1038/s41556-024-01468-x

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human tumor cell lines; 100 micromolar DFMO pretreatment and short HBSS starvation.

limitations

Pharmacological depletion differs from ordinary low dietary intake.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Blocking polyamine production can interrupt the fasting response.

primary_references

Spermidine is essential for fasting-mediated autophagy and longevity. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39117797/ · DOI 10.1038/s41556-024-01468-x

trigger_kind

machinery_impairment Imported condition classification; unverified.

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 182–188

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human tumor cell lines; 100 micromolar DFMO pretreatment and short HBSS starvation. · source_derived_draft · unverified_draft

## spermidine-fasting-odc Blocking polyamine production can interrupt the fasting response. DFMO inhibition of ODC1 reduced starvation-induced autophagic flux in U2OS and H4 cells. Model: Human tumor cell lines; 100 micromolar DFMO pretreatment and short HBSS starvation. Limitations: Pharmacological depletion differs from ordinary low dietary intake. Evidence access: Primary full text Spermidine is essential for fasting-mediated autophagy and longevity. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39117797/ · DOI 10.1038/s41556-024-01468-x

evidence_access

Primary full text

experimental_model

Human A549/HT1080 experiments; polyamine panel.

limitations

Does not negate GSH protection or generalize to every dose and cell type.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Iron-dependent injury did not require measured glutathione depletion.

primary_references

Polyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38504107/ · DOI 10.1038/s41467-024-46776-w

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human A549/HT1080 experiments; polyamine panel. · source_derived_draft · unverified_draft

## spermidine-ferroptosis-gsh-null Iron-dependent injury did not require measured glutathione depletion. Polyamine treatment did not deplete cellular glutathione in the reported comparison. Model: Human A549/HT1080 experiments; polyamine panel. Limitations: Does not negate GSH protection or generalize to every dose and cell type. Evidence access: Primary full text Polyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38504107/ · DOI 10.1038/s41467-024-46776-w

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Adult Drosophila genetic perturbations.

limitations

Model-specific; the companion brain papers have overlapping investigators and are not fully independent.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A pathway failure connects translation to brain energy use.

primary_references

eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33852845/ · DOI 10.1016/j.celrep.2021.108941

trigger_kind

machinery_impairment Imported condition classification; unverified.

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Adult Drosophila genetic perturbations. · source_derived_draft · unverified_draft

## spermidine-fly-hypusination A pathway failure connects translation to brain energy use. Genetic reduction of eIF5A hypusination impaired brain respiration and accelerated age-associated behavioral deficits. Model: Adult Drosophila genetic perturbations. Limitations: Model-specific; the companion brain papers have overlapping investigators and are not fully independent. Evidence access: Primary abstract eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33852845/ · DOI 10.1016/j.celrep.2021.108941

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Aging Drosophila genetic experiments.

limitations

Does not establish treatment of human PINK1-associated disease.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A mitophagy component was required for the learning response.

primary_references

Dietary spermidine improves cognitive function. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33852843/ · DOI 10.1016/j.celrep.2021.108985

trigger_kind

machinery_impairment Imported condition classification; unverified.

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Aging Drosophila genetic experiments. · source_derived_draft · unverified_draft

## spermidine-fly-pink1 A mitophagy component was required for the learning response. Neuron-specific Pink1 knockdown abolished spermidine-associated improvement of olfactory associative learning. Model: Aging Drosophila genetic experiments. Limitations: Does not establish treatment of human PINK1-associated disease. Evidence access: Primary abstract Dietary spermidine improves cognitive function. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33852843/ · DOI 10.1016/j.celrep.2021.108985

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse T-cell-transfer colitis with conditional deletions.

limitations

Mechanistic context difference, not an opposing scientific claim.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Which cell loses the protein changes the response.

primary_references

Spermidine Ameliorates Colitis via Induction of Anti-Inflammatory Macrophages and Prevention of Intestinal Dysbiosis. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36995738/ · DOI 10.1093/ecco-jcc/jjad058

trigger_kind

machinery_impairment Imported condition classification; unverified.

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse T-cell-transfer colitis with conditional deletions. · source_derived_draft · unverified_draft

## spermidine-gut-ptpn2 Which cell loses the protein changes the response. Loss of Ptpn2 in intestinal epithelial or myeloid cells abolished spermidine protection in the colitis model; T-cell loss did not. Model: Mouse T-cell-transfer colitis with conditional deletions. Limitations: Mechanistic context difference, not an opposing scientific claim. Evidence access: Primary full text Spermidine Ameliorates Colitis via Induction of Anti-Inflammatory Macrophages and Prevention of Intestinal Dysbiosis. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36995738/ · DOI 10.1093/ecco-jcc/jjad058

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Genetically modified mice.

limitations

A required pathway is not proof that autophagy alone explains all cardiac effects.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

The recycling machinery was required for this benefit.

primary_references

Cardioprotection and lifespan extension by the natural polyamine spermidine. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27841876/ · DOI 10.1038/nm.4222

trigger_kind

machinery_impairment Imported condition classification; unverified.

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Genetically modified mice. · source_derived_draft · unverified_draft

## spermidine-heart-atg5 The recycling machinery was required for this benefit. Cardiomyocyte-specific Atg5 loss abolished the reported cardioprotective response to spermidine. Model: Genetically modified mice. Limitations: A required pathway is not proof that autophagy alone explains all cardiac effects. Evidence access: Primary abstract Cardioprotection and lifespan extension by the natural polyamine spermidine. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27841876/ · DOI 10.1038/nm.4222

evidence_access

Primary full text

experimental_model

Human prostate cancer combination-treatment model.

limitations

NRF2/HMOX1 direction depends on cell state and iron handling; no universal ferroptosis prediction.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Heme breakdown links this response to iron availability.

primary_references

Spermidine inactivates proteasome activity and enhances ferroptosis in prostate cancer. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40486852/ · DOI 10.1016/j.apsb.2025.02.023

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human prostate cancer combination-treatment model. · source_derived_draft · unverified_draft

## spermidine-hmox1-iron Heme breakdown links this response to iron availability. The study linked elevated NRF2 to HMOX1 upregulation and increased labile ferrous iron during combination treatment. Model: Human prostate cancer combination-treatment model. Limitations: NRF2/HMOX1 direction depends on cell state and iron handling; no universal ferroptosis prediction. Evidence access: Primary full text Spermidine inactivates proteasome activity and enhances ferroptosis in prostate cancer. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40486852/ · DOI 10.1016/j.apsb.2025.02.023

evidence_access

Primary abstract

experimental_model

Purified human DHPS comparison of deoxyhypusine and hypusine protein substrates.

limitations

Assay-specific non-reversal does not establish lifetime stability of the protein.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

The second modification step stabilizes the completed product.

primary_references

Reversal of the deoxyhypusine synthesis reaction. Generation of spermidine or homospermidine from deoxyhypusine by deoxyhypusine synthase. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12788913/ · DOI 10.1074/jbc.M304247200

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 46–52

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human DHPS comparison of deoxyhypusine and hypusine protein substrates. · source_derived_draft · unverified_draft

## spermidine-hydroxylation-lock The second modification step stabilizes the completed product. The same reversal assay did not remove the side chain from hypusine-containing eIF5A. Model: Purified human DHPS comparison of deoxyhypusine and hypusine protein substrates. Limitations: Assay-specific non-reversal does not establish lifetime stability of the protein. Evidence access: Primary abstract Reversal of the deoxyhypusine synthesis reaction. Generation of spermidine or homospermidine from deoxyhypusine by deoxyhypusine synthase. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12788913/ · DOI 10.1074/jbc.M304247200

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse AML12 cells; genetic knockdown and rescue design.

limitations

Does not imply that all low DOHH activity is caused by iron deficiency.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

More spermidine could not bypass the missing enzyme.

primary_references

Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36057633/ · DOI 10.1038/s41467-022-32788-x

trigger_kind

machinery_impairment Imported condition classification; unverified.

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse AML12 cells; genetic knockdown and rescue design. · source_derived_draft · unverified_draft

## spermidine-liver-dohh-failure More spermidine could not bypass the missing enzyme. Dohh siRNA prevented spermidine rescue of mitochondrial protein expression and respiration under fatty-acid stress. Model: Mouse AML12 cells; genetic knockdown and rescue design. Limitations: Does not imply that all low DOHH activity is caused by iron deficiency. Evidence access: Primary full text Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36057633/ · DOI 10.1038/s41467-022-32788-x

evidence_access

Primary full text

experimental_model

Human liver expression comparison.

limitations

Association is not enzyme-activity measurement or proof that spermidine treats NASH.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Human tissue provides an association to test.

primary_references

Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36057633/ · DOI 10.1038/s41467-022-32788-x

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human liver expression comparison. · source_derived_draft · unverified_draft

## spermidine-liver-nash-marker Human tissue provides an association to test. Hepatic DOHH mRNA was lower in sampled patients with NASH. Model: Human liver expression comparison. Limitations: Association is not enzyme-activity measurement or proof that spermidine treats NASH. Evidence access: Primary full text Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36057633/ · DOI 10.1038/s41467-022-32788-x

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse bone-marrow-derived macrophages; 10 micromolar GC7 for 24 hours in the tracing experiment.

limitations

GC7 can have off-target effects; accompanying genetic experiments strengthen but do not make every effect specific.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Blocking the translation pathway changes fuel use.

primary_references

Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31130465/ · DOI 10.1016/j.cmet.2019.05.003

trigger_kind

machinery_impairment Imported condition classification; unverified.

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 262–268

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse bone-marrow-derived macrophages; 10 micromolar GC7 for 24 hours in the tracing experiment. · source_derived_draft · unverified_draft

## spermidine-macrophage-respiration Blocking the translation pathway changes fuel use. GC7 inhibition of hypusination reduced oxidative phosphorylation in IL-4-activated mouse macrophages. Model: Mouse bone-marrow-derived macrophages; 10 micromolar GC7 for 24 hours in the tracing experiment. Limitations: GC7 can have off-target effects; accompanying genetic experiments strengthen but do not make every effect specific. Evidence access: Primary full text Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31130465/ · DOI 10.1016/j.cmet.2019.05.003

evidence_access

Primary abstract

experimental_model

Bacterial culture; homospermidine and, less strongly, norspermidine rescue.

limitations

Do not turn a bacterial growth result into a human infection-risk estimate.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Polyamines can support microbial growth, including a pathogen.

primary_references

Alternative spermidine biosynthetic route is critical for growth of Campylobacter jejuni and is the dominant polyamine pathway in human gut microbiota. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22025614/ · DOI 10.1074/jbc.M111.307835

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Bacterial culture; homospermidine and, less strongly, norspermidine rescue. · source_derived_draft · unverified_draft

## spermidine-microbial-growth Polyamines can support microbial growth, including a pathogen. Polyamine-auxotrophic Campylobacter deletion strains grew poorly; supplied related polyamines could rescue growth. Model: Bacterial culture; homospermidine and, less strongly, norspermidine rescue. Limitations: Do not turn a bacterial growth result into a human infection-risk estimate. Evidence access: Primary abstract Alternative spermidine biosynthetic route is critical for growth of Campylobacter jejuni and is the dominant polyamine pathway in human gut microbiota. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22025614/ · DOI 10.1074/jbc.M111.307835

evidence_access

Primary full text

experimental_model

Mouse macrophage/MEF protein experiments and targeting-sequence reporters.

limitations

This is protein expression, not proof of riboflavin, CoA or B12 deficiency; the relevant cofactor requires separate evidence.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Making a cofactor-dependent enzyme is another potential bottleneck.

primary_references

Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31130465/ · DOI 10.1016/j.cmet.2019.05.003

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse macrophage/MEF protein experiments and targeting-sequence reporters. · source_derived_draft · unverified_draft

## spermidine-mitochondrial-target-mmut Making a cofactor-dependent enzyme is another potential bottleneck. Hypusination disruption lowered expression of methylmalonyl-CoA mutase; its mitochondrial targeting sequence increased reporter dependence on eIF5A. Model: Mouse macrophage/MEF protein experiments and targeting-sequence reporters. Limitations: This is protein expression, not proof of riboflavin, CoA or B12 deficiency; the relevant cofactor requires separate evidence. Evidence access: Primary full text Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31130465/ · DOI 10.1016/j.cmet.2019.05.003

evidence_access

Primary full text

experimental_model

Mouse macrophage/MEF protein experiments and targeting-sequence reporters.

limitations

This is protein expression, not proof of riboflavin, CoA or B12 deficiency; the relevant cofactor requires separate evidence.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Making a cofactor-dependent enzyme is another potential bottleneck.

primary_references

Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31130465/ · DOI 10.1016/j.cmet.2019.05.003

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse macrophage/MEF protein experiments and targeting-sequence reporters. · source_derived_draft · unverified_draft

## spermidine-mitochondrial-target-sdha Making a cofactor-dependent enzyme is another potential bottleneck. Hypusination disruption lowered expression of succinate dehydrogenase subunit A; its mitochondrial targeting sequence increased reporter dependence on eIF5A. Model: Mouse macrophage/MEF protein experiments and targeting-sequence reporters. Limitations: This is protein expression, not proof of riboflavin, CoA or B12 deficiency; the relevant cofactor requires separate evidence. Evidence access: Primary full text Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31130465/ · DOI 10.1016/j.cmet.2019.05.003

evidence_access

Primary full text

experimental_model

Mouse macrophage/MEF protein experiments and targeting-sequence reporters.

limitations

This is protein expression, not proof of riboflavin, CoA or B12 deficiency; the relevant cofactor requires separate evidence.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Making a cofactor-dependent enzyme is another potential bottleneck.

primary_references

Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31130465/ · DOI 10.1016/j.cmet.2019.05.003

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse macrophage/MEF protein experiments and targeting-sequence reporters. · source_derived_draft · unverified_draft

## spermidine-mitochondrial-target-suclg1 Making a cofactor-dependent enzyme is another potential bottleneck. Hypusination disruption lowered expression of succinyl-CoA ligase alpha; its mitochondrial targeting sequence increased reporter dependence on eIF5A. Model: Mouse macrophage/MEF protein experiments and targeting-sequence reporters. Limitations: This is protein expression, not proof of riboflavin, CoA or B12 deficiency; the relevant cofactor requires separate evidence. Evidence access: Primary full text Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31130465/ · DOI 10.1016/j.cmet.2019.05.003

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse satellite-cell genetic experiments.

limitations

Cell activation and long-term functional muscle repair are distinct outcomes.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

The downstream protein was itself necessary.

primary_references

Spermidine-eIF5A axis is essential for muscle stem cell activation via translational control. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39251577/ · DOI 10.1038/s41421-024-00712-w

trigger_kind

machinery_impairment Imported condition classification; unverified.

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 390–396

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse satellite-cell genetic experiments. · source_derived_draft · unverified_draft

## spermidine-myod-required The downstream protein was itself necessary. Myod knockout prevented the spermidine-associated satellite-cell activation response. Model: Mouse satellite-cell genetic experiments. Limitations: Cell activation and long-term functional muscle repair are distinct outcomes. Evidence access: Primary full text Spermidine-eIF5A axis is essential for muscle stem cell activation via translational control. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39251577/ · DOI 10.1038/s41421-024-00712-w

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse satellite-cell knockout, ribosome profiling and translation experiments.

limitations

Dependency does not show that every muscle protein is similarly regulated.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A specific muscle-regulating protein is a translation target.

primary_references

Spermidine-eIF5A axis is essential for muscle stem cell activation via translational control. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39251577/ · DOI 10.1038/s41421-024-00712-w

trigger_kind

machinery_impairment Imported condition classification; unverified.

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 382–388

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse satellite-cell knockout, ribosome profiling and translation experiments. · source_derived_draft · unverified_draft

## spermidine-myod-translation A specific muscle-regulating protein is a translation target. Satellite-cell eIF5A knockout reduced MyoD translation and impaired the spermidine-associated activation response. Model: Mouse satellite-cell knockout, ribosome profiling and translation experiments. Limitations: Dependency does not show that every muscle protein is similarly regulated. Evidence access: Primary full text Spermidine-eIF5A axis is essential for muscle stem cell activation via translational control. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39251577/ · DOI 10.1038/s41421-024-00712-w

evidence_access

Primary abstract

experimental_model

Receptor uptake assays in defined ionic solutions.

limitations

No dietary calcium–spermidine antagonism established.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Ions and polyamines can affect each other’s channel passage.

primary_references

Spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg(2+). · 2015 · https://pubmed.ncbi.nlm.nih.gov/26086092/ · DOI 10.1016/j.bbrc.2015.06.081

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Receptor uptake assays in defined ionic solutions. · source_derived_draft · unverified_draft

## spermidine-nmda-calcium Ions and polyamines can affect each other’s channel passage. Calcium inhibited spermidine uptake through the tested NMDA receptors. Model: Receptor uptake assays in defined ionic solutions. Limitations: No dietary calcium–spermidine antagonism established. Evidence access: Primary abstract Spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg(2+). · 2015 · https://pubmed.ncbi.nlm.nih.gov/26086092/ · DOI 10.1016/j.bbrc.2015.06.081

evidence_access

Primary abstract

experimental_model

Heterologous receptor transport assays.

limitations

Requirement is for receptor activation, not evidence for an oral supplement combination.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Other amino acids gate this entry route.

primary_references

Spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg(2+). · 2015 · https://pubmed.ncbi.nlm.nih.gov/26086092/ · DOI 10.1016/j.bbrc.2015.06.081

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Heterologous receptor transport assays. · source_derived_draft · unverified_draft

## spermidine-nmda-ligands Other amino acids gate this entry route. Spermidine uptake through the tested NMDA receptors required glycine and glutamate. Model: Heterologous receptor transport assays. Limitations: Requirement is for receptor activation, not evidence for an oral supplement combination. Evidence access: Primary abstract Spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg(2+). · 2015 · https://pubmed.ncbi.nlm.nih.gov/26086092/ · DOI 10.1016/j.bbrc.2015.06.081

evidence_access

Primary abstract

experimental_model

Defined receptor assay solutions.

limitations

Voltage and ionic conditions are essential; no general claim that spermidine bypasses all NMDA magnesium block.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A magnesium block is not identical for every permeating species.

primary_references

Spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg(2+). · 2015 · https://pubmed.ncbi.nlm.nih.gov/26086092/ · DOI 10.1016/j.bbrc.2015.06.081

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Defined receptor assay solutions. · source_derived_draft · unverified_draft

## spermidine-nmda-magnesium A magnesium block is not identical for every permeating species. Spermidine and calcium influx persisted under magnesium conditions that strongly inhibited sodium influx. Model: Defined receptor assay solutions. Limitations: Voltage and ionic conditions are essential; no general claim that spermidine bypasses all NMDA magnesium block. Evidence access: Primary abstract Spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg(2+). · 2015 · https://pubmed.ncbi.nlm.nih.gov/26086092/ · DOI 10.1016/j.bbrc.2015.06.081

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human cancer-cell genetic experiments; mixed polyamine comparisons.

limitations

Polyamine-class result; do not attribute all experiments to spermidine alone.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Oxidative breakdown provides another route to lipid injury.

primary_references

Polyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38504107/ · DOI 10.1038/s41467-024-46776-w

trigger_kind

machinery_impairment Imported condition classification; unverified.

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 534–540

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell genetic experiments; mixed polyamine comparisons. · source_derived_draft · unverified_draft

## spermidine-oxidase-ferroptosis Oxidative breakdown provides another route to lipid injury. PAOX/SMOX knockout reduced polyamine-associated sensitization to ferroptosis in A549 and HT1080 cells. Model: Human cancer-cell genetic experiments; mixed polyamine comparisons. Limitations: Polyamine-class result; do not attribute all experiments to spermidine alone. Evidence access: Primary full text Polyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38504107/ · DOI 10.1038/s41467-024-46776-w

evidence_access

Primary abstract

experimental_model

Purified human enzyme.

limitations

Do not apply these values to unmodified spermidine or a human plasma target.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

The acetylated molecule has its own enzyme kinetics.

primary_references

Properties of recombinant human N1-acetylpolyamine oxidase (hPAO): potential role in determining drug sensitivity. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15791459/ · DOI 10.1007/s00280-004-0936-5

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 94–100

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human enzyme. · source_derived_draft · unverified_draft

## spermidine-paox-acetylspermidine The acetylated molecule has its own enzyme kinetics. Recombinant human PAOX oxidized N1-acetylspermidine with Km 2.1 micromolar and kcat 15 per second. Model: Purified human enzyme. Limitations: Do not apply these values to unmodified spermidine or a human plasma target. Evidence access: Primary abstract Properties of recombinant human N1-acetylpolyamine oxidase (hPAO): potential role in determining drug sensitivity. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15791459/ · DOI 10.1007/s00280-004-0936-5

evidence_access

Primary abstract

experimental_model

Purified human enzyme.

limitations

Substrate specificity differs from SMOX; enzyme turnover is not whole-body turnover.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Back-conversion depends on which polyamine was acetylated.

primary_references

Properties of recombinant human N1-acetylpolyamine oxidase (hPAO): potential role in determining drug sensitivity. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15791459/ · DOI 10.1007/s00280-004-0936-5

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 102–108

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human enzyme. · source_derived_draft · unverified_draft

## spermidine-paox-acetylspermine Back-conversion depends on which polyamine was acetylated. Human PAOX oxidized N1-acetylspermine with Km 0.85 micromolar and kcat 31.7 per second. Model: Purified human enzyme. Limitations: Substrate specificity differs from SMOX; enzyme turnover is not whole-body turnover. Evidence access: Primary abstract Properties of recombinant human N1-acetylpolyamine oxidase (hPAO): potential role in determining drug sensitivity. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15791459/ · DOI 10.1007/s00280-004-0936-5

evidence_access

Primary abstract

experimental_model

Purified enzyme comparison.

limitations

Do not substitute PAOX for SMOX in the graph.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Acetylation changes substrate recognition.

primary_references

Properties of recombinant human N1-acetylpolyamine oxidase (hPAO): potential role in determining drug sensitivity. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15791459/ · DOI 10.1007/s00280-004-0936-5

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 110–116

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified enzyme comparison. · source_derived_draft · unverified_draft

## spermidine-paox-spermine-null Acetylation changes substrate recognition. The recombinant human PAOX preparation did not efficiently oxidize unacetylated spermine. Model: Purified enzyme comparison. Limitations: Do not substitute PAOX for SMOX in the graph. Evidence access: Primary abstract Properties of recombinant human N1-acetylpolyamine oxidase (hPAO): potential role in determining drug sensitivity. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15791459/ · DOI 10.1007/s00280-004-0936-5

evidence_access

Primary abstract

experimental_model

Human SAT1 initial-velocity, inhibition and pH experiments.

limitations

Mechanism does not quantify whole-body acetyl-CoA competition.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Both the donor and the polyamine must reach the enzyme.

primary_references

Mechanistic and structural analysis of human spermidine/spermine N1-acetyltransferase. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17516632/ · DOI 10.1021/bi700256z

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 86–92

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human SAT1 initial-velocity, inhibition and pH experiments. · source_derived_draft · unverified_draft

## spermidine-sat1-cosubstrate Both the donor and the polyamine must reach the enzyme. Human SAT1 kinetics support a random sequential mechanism involving acetyl donor and polyamine in a ternary complex. Model: Human SAT1 initial-velocity, inhibition and pH experiments. Limitations: Mechanism does not quantify whole-body acetyl-CoA competition. Evidence access: Primary abstract Mechanistic and structural analysis of human spermidine/spermine N1-acetyltransferase. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17516632/ · DOI 10.1021/bi700256z

evidence_access

Primary abstract

experimental_model

1984 serum and oxygen-tension comparison; micromolar exposure range.

limitations

Historical serum oxidase activity is not automatically modern human SMOX identity.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Blocking extracellular oxidation changed the result.

primary_references

Spermidine cytotoxicity in vitro: effect of serum and oxygen tension. · 1984 · https://pubmed.ncbi.nlm.nih.gov/6715006/ · DOI 10.1007/BF02618188

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 494–500

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 1984 serum and oxygen-tension comparison; micromolar exposure range. · source_derived_draft · unverified_draft

## spermidine-serum-toxicity-rescue Blocking extracellular oxidation changed the result. Aminoguanidine prevented spermidine-associated cytotoxicity in the serum-containing NS1-cell experiment. Model: 1984 serum and oxygen-tension comparison; micromolar exposure range. Limitations: Historical serum oxidase activity is not automatically modern human SMOX identity. Evidence access: Primary abstract Spermidine cytotoxicity in vitro: effect of serum and oxygen tension. · 1984 · https://pubmed.ncbi.nlm.nih.gov/6715006/ · DOI 10.1007/BF02618188

evidence_access

Primary full text

experimental_model

Single-turnover fluorescence and structural assays; apparent spermine KD about 81 micromolar.

limitations

The assay probes an initial reaction step, not successful cellular replacement of spermidine for complete eIF5A hypusination.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A related polyamine can participate in part of the chemistry.

primary_references

Half Way to Hypusine-Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32235505/ · DOI 10.3390/biom10040522

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 30–36

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Single-turnover fluorescence and structural assays; apparent spermine KD about 81 micromolar. · source_derived_draft · unverified_draft

## spermidine-spermine-first-step A related polyamine can participate in part of the chemistry. Spermine bound human DHPS and generated a smaller NADH fluorescence response than spermidine. Model: Single-turnover fluorescence and structural assays; apparent spermine KD about 81 micromolar. Limitations: The assay probes an initial reaction step, not successful cellular replacement of spermidine for complete eIF5A hypusination. Evidence access: Primary full text Half Way to Hypusine-Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32235505/ · DOI 10.3390/biom10040522

evidence_access

Primary full text

experimental_model

Murine TFEB constructs in NIH 3T3 cells.

limitations

Partial rescue; free proline supplementation was not tested.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A sequence within the protein helps explain the dependency.

primary_references

Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31474573/ · DOI 10.1016/j.molcel.2019.08.005

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 222–228

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Murine TFEB constructs in NIH 3T3 cells. · source_derived_draft · unverified_draft

## spermidine-tfeb-proline A sequence within the protein helps explain the dependency. Replacing the TFEB PPP motif with AAA partially rescued TFEB expression during GC7 treatment. Model: Murine TFEB constructs in NIH 3T3 cells. Limitations: Partial rescue; free proline supplementation was not tested. Evidence access: Primary full text Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31474573/ · DOI 10.1016/j.molcel.2019.08.005

evidence_access

Primary full text

experimental_model

Mouse cellular experiments with translation labeling and hypusination perturbation.

limitations

Requirement is transcript- and context-dependent, not equal enhancement of all proteins.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Spermidine helps produce a regulator of cellular recycling.

primary_references

Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31474573/ · DOI 10.1016/j.molcel.2019.08.005

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 214–220

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse cellular experiments with translation labeling and hypusination perturbation. · source_derived_draft · unverified_draft

## spermidine-tfeb-translation Spermidine helps produce a regulator of cellular recycling. Disrupting eIF5A hypusination reduced nascent TFEB synthesis in the B-cell/autophagy study. Model: Mouse cellular experiments with translation labeling and hypusination perturbation. Limitations: Requirement is transcript- and context-dependent, not equal enhancement of all proteins. Evidence access: Primary full text Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31474573/ · DOI 10.1016/j.molcel.2019.08.005

experimental_model

Human DHPS structural biochemistry.

limitations

NAD cycles during catalysis; it is not represented as a net consumed substrate here. This reaction modifies lysine already in a protein. It does not show that extra oral lysine increases the reaction or improves a clinical outcome.

organism

Human

plain_language

A particular protein lysine becomes a specialized translation-factor residue.

primary_references

[dhps-2020] Half Way to Hypusine-Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase (2020). https://pubmed.ncbi.nlm.nih.gov/32235505/

tissue_or_cell_type

Not specified as a whole tissue; see experimental model.

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 578–586

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human DHPS structural biochemistry. · source_derived_draft · unverified_draft

### dhps-eif5a-deoxyhypusine DHPS transfers spermidine-derived aminobutyl onto eIF5A Lys50 to form deoxyhypusine. Plain language: A particular protein lysine becomes a specialized translation-factor residue. Condition category: normal organism: Human tissue_or_cell_type: Not specified as a whole tissue; see experimental model. experimental_model: Human DHPS structural biochemistry. limitations: NAD cycles during catalysis; it is not represented as a net consumed substrate here. This reaction modifies lysine already in a protein. It does not show that extra oral lysine increases the reaction or improves a clinical outcome. [dhps-2020] Half Way to Hypusine-Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase (2020). https://pubmed.ncbi.nlm.nih.gov/32235505/