Nutrient chapter

Spermidine

Spermidine is a polyamine supplied by cellular synthesis, food and microbes. Explore NAD- and iron-dependent hypusination, amino-acid and SAM metabolism, transport, autophagy, immune cells, mitochondrial proteins and ion channels. Human trial results, failed rescues and experimental limitations are retained. No human dietary spermidine-deficiency threshold is established.

87 recorded mechanisms · 15 availability situations · 9 preserved sources. Draft and verified records are labeled separately.

Read recorded mechanisms Open recursive mind map

The mechanisms

What the sources say this nutrient does, one relationship at a time. Plain wording comes first; the technical statement follows.

Human DHPS binds NAD and spermidine; NAD-dependent chemistry initiates aminobutyl transfer.
NAD+ → DHPS source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The human DHPS study measured an apparent spermidine binding KD of about 4 micromolar using the reported FRET assay.
Spermidine → DHPS source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 22–28
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
Complete structured claim and evidence
Spermine bound human DHPS and generated a smaller NADH fluorescence response than spermidine.
Spermine → DHPS source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Purified human DHPS transferred radiolabeled aminobutyl from deoxyhypusine-eIF5A to 1,3-diaminopropane, regenerating spermidine.
DHPS → Spermidine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The same reversal assay did not remove the side chain from hypusine-containing eIF5A.
eIF5A1 with hypusine at residue 50 → DHPS source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Spectroscopy established a coupled diiron center in human DOHH, whose reduced state activates oxygen.
Ferrous iron → DOHH source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human DOHH structures resolved a peroxo-diiron intermediate involved in hydroxylating deoxyhypusine-eIF5A.
Molecular oxygen → DOHH source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Spermidine inhibited rat-testis deoxyhypusine hydroxylase in vitro, less potently than spermine.
Spermidine → Rat deoxyhypusine hydroxylase / Dohh source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 70–76
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
Complete structured claim and evidence
Human SAT1 catalyzes N1-acetylation of spermidine using acetyl-CoA.
Human spermidine/spermine N1-acetyltransferase / SAT1 → Spermidine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human SAT1 kinetics support a random sequential mechanism involving acetyl donor and polyamine in a ternary complex.
Acetyl-CoA → Human spermidine/spermine N1-acetyltransferase / SAT1 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Recombinant human PAOX oxidized N1-acetylspermidine with Km 2.1 micromolar and kcat 15 per second.
Human N1-acetylpolyamine oxidase / PAOX → N1-Acetylspermidine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human PAOX oxidized N1-acetylspermine with Km 0.85 micromolar and kcat 31.7 per second.
Human N1-acetylpolyamine oxidase / PAOX → N1-Acetylspermine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The recombinant human PAOX preparation did not efficiently oxidize unacetylated spermine.
Human N1-acetylpolyamine oxidase / PAOX → Spermine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
ATP13A2 supports lysosomal polyamine export to cytosol after endocytic uptake; spermine had the highest tested affinity.
Human ATP13A2 / PARK9 → Human lysosome-to-cytosol polyamine export source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Loss or disease-associated impairment of ATP13A2 reduced export function and worsened high-polyamine lysosomal injury.
Human ATP13A2 / PARK9 → Human lysosome-to-cytosol polyamine export source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
CRISPR disruption of the first membrane-associated region of ATP13A3 impaired spermidine transport in human pancreatic cancer cells.
Human ATP13A3 → Spermidine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Purified human SLC18B1 transported spermidine into proteoliposomes by proton exchange.
Human vesicular polyamine transporter / SLC18B1 → Spermidine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Spermidine inhibited acetyltransferase activity of recombinant EP300 in vitro.
Spermidine → EP300 source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 150–156
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
Complete structured claim and evidence
Spermidine induced autophagic-flux markers, including GFP-LC3 puncta and p62 depletion, in cultured human cells.
Spermidine → Human cultured-cell autophagic flux source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 158–164
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
Complete structured claim and evidence
Spermidine-associated autophagy induction coincided with inhibition of mTORC1 signaling in the human-cell study.
Spermidine → Mechanistic target of rapamycin complex 1 source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 166–172
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
Complete structured claim and evidence
EP300 knockdown induced autophagy and reduced mTORC1 activity in the acetyltransferase screen.
EP300 → Human cultured-cell autophagic flux source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
DFMO inhibition of ODC1 reduced starvation-induced autophagic flux in U2OS and H4 cells.
Human ornithine decarboxylase / ODC1 → Human U2OS/H4 starvation-induced autophagic flux source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Added spermidine rescued autophagic-flux suppression caused by DFMO during starvation.
Spermidine → Human U2OS/H4 starvation-induced autophagic flux source_derived_draftungraded
Experimental context and source evidence
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.
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 190–196
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
Complete structured claim and evidence
Three ODC1-directed siRNAs depleted polyamines and reduced starvation-induced autophagic flux.
Human ornithine decarboxylase / ODC1 → Human U2OS/H4 starvation-induced autophagic flux source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
PBMC hypusinated eIF5A increased during the studied multiday fasting regimen and remained elevated after food reintroduction.
Human prolonged-fasting study exposure → Human PBMC eIF5A hypusination source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Disrupting eIF5A hypusination reduced nascent TFEB synthesis in the B-cell/autophagy study.
Mouse eIF5A translation factor → Mouse transcription factor EB / Tfeb source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Replacing the TFEB PPP motif with AAA partially rescued TFEB expression during GC7 treatment.
Mouse TFEB triproline-containing translation motif → Mouse transcription factor EB / Tfeb source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Spermidine supplementation restored the hypusination–TFEB–autophagy pathway and improved old-donor B-cell responses ex vivo.
Spermidine → Human older-donor B-cell response ex vivo source_derived_draftungraded
Experimental context and source evidence
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.
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 230–236
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
Complete structured claim and evidence
Adding spermidine restored autophagic flux in stimulated T cells from older human donors.
Spermidine → Human older-donor CD8 T-cell autophagy source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Spermidine restored TFEB protein and eIF5A hypusination in older-donor CD8 cells and in DFMO-treated young-donor cells.
Spermidine → Human transcription factor EB / TFEB source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Spermidine improved effector-function readouts in cultured T cells from older donors.
Spermidine → Human older-donor T-cell effector response ex vivo source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
GC7 inhibition of hypusination reduced oxidative phosphorylation in IL-4-activated mouse macrophages.
Mouse deoxyhypusine synthase / Dhps → Mouse macrophage oxidative phosphorylation source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Hypusination disruption lowered expression of succinate dehydrogenase subunit A; its mitochondrial targeting sequence increased reporter dependence on eIF5A.
Mouse eIF5A translation factor → Mouse succinate dehydrogenase subunit A / SDHA source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 270–276
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
Complete structured claim and evidence
Hypusination disruption lowered expression of succinyl-CoA ligase alpha; its mitochondrial targeting sequence increased reporter dependence on eIF5A.
Mouse eIF5A translation factor → Mouse succinyl-CoA ligase alpha / SUCLG1 source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 278–284
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
Complete structured claim and evidence
Hypusination disruption lowered expression of methylmalonyl-CoA mutase; its mitochondrial targeting sequence increased reporter dependence on eIF5A.
Mouse eIF5A translation factor → Mouse methylmalonyl-CoA mutase / MMUT source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 286–292
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
Complete structured claim and evidence
Acute inhibition of hypusination impaired alternative macrophage activation while largely sparing glycolysis-associated classical activation.
Mouse deoxyhypusine synthase / Dhps → Mouse IL-4-associated macrophage activation source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Spermidine partially restored protein synthesis and mitochondrial respiration in fatty-acid-treated AML12 cells.
Spermidine → Mouse AML12 mitochondrial respiration source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 302–308
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
Complete structured claim and evidence
Dohh siRNA prevented spermidine rescue of mitochondrial protein expression and respiration under fatty-acid stress.
Mouse deoxyhypusine hydroxylase / Dohh → Mouse AML12 mitochondrial respiration source_derived_draftungraded
Experimental context and source evidence
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.
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 310–316
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
Complete structured claim and evidence
Hepatic DOHH mRNA was lower in sampled patients with NASH.
Human NASH liver sampling context → DOHH source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 318–324
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
Complete structured claim and evidence
Oral spermidine enhanced cardiac autophagy, mitophagy and mitochondrial respiration in the mouse aging study.
Spermidine → Mouse cardiac autophagy and mitophagy source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 326–332
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
Complete structured claim and evidence
Cardiomyocyte-specific Atg5 loss abolished the reported cardioprotective response to spermidine.
Mouse autophagy related 5 / Atg5 → Mouse spermidine-associated cardiac protection source_derived_draftungraded
Experimental context and source evidence
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.
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 334–340
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
Complete structured claim and evidence
Spermidine increased titin phosphorylation in high-salt-fed Dahl salt-sensitive rats.
Spermidine → Rat titin / Ttn source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The mouse study reported brain entry of dietary spermidine and increased hippocampal eIF5A hypusination.
Spermidine → Mouse brain spermidine exposure source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 350–356
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
Complete structured claim and evidence
Neuron-specific Pink1 knockdown abolished spermidine-associated improvement of olfactory associative learning.
Drosophila melanogaster Pink1 → Drosophila spermidine-associated olfactory learning response source_derived_draftungraded
Experimental context and source evidence
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.
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 358–364
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
Complete structured claim and evidence
Genetic reduction of eIF5A hypusination impaired brain respiration and accelerated age-associated behavioral deficits.
Drosophila eIF5A hypusination → Drosophila brain mitochondrial respiration source_derived_draftungraded
Experimental context and source evidence
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.
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 366–372
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
Complete structured claim and evidence
Spermidine promoted muscle satellite-cell activation and regeneration in mice.
Spermidine → Mouse muscle satellite-cell activation source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Satellite-cell eIF5A knockout reduced MyoD translation and impaired the spermidine-associated activation response.
Mouse eIF5A translation factor → Mouse myogenic differentiation 1 / Myod1 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Myod knockout prevented the spermidine-associated satellite-cell activation response.
Mouse myogenic differentiation 1 / Myod1 → Mouse muscle satellite-cell activation source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Loss of Ptpn2 in intestinal epithelial or myeloid cells abolished spermidine protection in the colitis model; T-cell loss did not.
Mouse protein tyrosine phosphatase non-receptor 2 / Ptpn2 → Mouse spermidine-associated colitis and barrier response source_derived_draftungraded
Experimental context and source evidence
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.
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 398–404
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
Complete structured claim and evidence
Spermidine preserved barrier readouts in LPS-challenged epithelial–macrophage cocultures in a PTPN2-dependent setting.
Spermidine → Human Caco-2/macrophage coculture barrier integrity source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 406–412
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
Complete structured claim and evidence
Deleting the carboxypolyamine-decarboxylase orthologue disrupted spermidine synthesis in Campylobacter jejuni.
Campylobacter jejuni carboxyspermidine decarboxylase → Spermidine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Polyamine-auxotrophic Campylobacter deletion strains grew poorly; supplied related polyamines could rescue growth.
Campylobacter jejuni carboxyspermidine decarboxylase → Campylobacter jejuni growth source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 422–428
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
Complete structured claim and evidence
Cytoplasmic spermidine caused reversible voltage-dependent rectification of cloned HRK1 channels.
Spermidine → HRK1 inward-rectifier potassium channel in the cloned-channel assay source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 430–436
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
Complete structured claim and evidence
Magnesium-associated unblock was almost instantaneous, whereas spermidine unblock was time dependent.
Mg2+ → Spermidine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Spermidine permeated activated GluN1/GluN2A and GluN1/GluN2B channels; reported Km values were 2.2 and 2.7 mM.
GluN1/GluN2A or GluN1/GluN2B NMDA receptor permeation assay; construct species unresolved → Spermidine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Spermidine uptake through the tested NMDA receptors required glycine and glutamate.
Glycine → GluN1/GluN2A or GluN1/GluN2B NMDA receptor permeation assay; construct species unresolved source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 454–460
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
Complete structured claim and evidence
Calcium inhibited spermidine uptake through the tested NMDA receptors.
Calcium ion → GluN1/GluN2A or GluN1/GluN2B NMDA receptor permeation assay; construct species unresolved source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 462–468
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
Complete structured claim and evidence
Spermidine and calcium influx persisted under magnesium conditions that strongly inhibited sodium influx.
Mg2+ → GluN1/GluN2A or GluN1/GluN2B NMDA receptor permeation assay; construct species unresolved source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 470–476
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
Complete structured claim and evidence
Spermidine stimulated OAZ1 +1 frameshifting in engineered yeast; its response lacked the cooperativity seen with putrescine and spermine.
Spermidine → Saccharomyces cerevisiae Oaz1 antizyme source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 478–484
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
Complete structured claim and evidence
Added spermidine generated hydrogen peroxide in several animal-serum-containing media but not the tested human-serum medium.
Spermidine → Serum-mediated polyamine oxidation in cell culture source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Aminoguanidine prevented spermidine-associated cytotoxicity in the serum-containing NS1-cell experiment.
Aminoguanidine → NS1-cell serum-dependent spermidine cytotoxicity source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
One micromolar spermidine enhanced erastin-associated lipid peroxidation and cell death in PC3 and DU145 cells.
Spermidine → Human PC3/DU145 spermidine–erastin ferroptosis response source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 502–508
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
Complete structured claim and evidence
The prostate-cell study linked spermidine-driven eIF5A hypusination to increased NRF2 translation.
Spermidine → Human Nrf2 / NFE2L2 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Spermidine/erastin treatment reduced proteasome activity and NRF2 degradation in the reported prostate-cell experiments.
Spermidine → Human prostate-cell proteasome activity source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The study linked elevated NRF2 to HMOX1 upregulation and increased labile ferrous iron during combination treatment.
Human Nrf2 / NFE2L2 → Human heme oxygenase 1 / HMOX1 source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 526–532
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
Complete structured claim and evidence
PAOX/SMOX knockout reduced polyamine-associated sensitization to ferroptosis in A549 and HT1080 cells.
Human N1-acetylpolyamine oxidase / PAOX → Human A549/HT1080 polyamine-associated ferroptosis source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Polyamine treatment did not deplete cellular glutathione in the reported comparison.
Polyamine treatment in the A549/HT1080 ferroptosis study → GSH source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 542–548
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
Complete structured claim and evidence
Oral 15 mg/day spermidine for five days did not significantly increase plasma spermidine or putrescine versus placebo.
Spermidine → Human plasma spermidine concentration source_derived_draftungraded
Experimental context and source evidence
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.
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 550–556
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
Complete structured claim and evidence
The same trial found increased plasma spermine exposure after oral spermidine.
Spermidine → Human plasma spermine concentration source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Twelve months of wheat-germ extract supplying 0.9 mg/day spermidine did not significantly improve the primary memory outcome versus placebo.
Spermidine → Human SmartAge mnemonic discrimination performance source_derived_draftungraded
Experimental context and source evidence
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
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 566–572
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
Complete structured claim and evidence
DHPS transfers spermidine-derived aminobutyl onto eIF5A Lys50 to form deoxyhypusine.
DHPS → eIF5A1 with unmodified Lys50 source_derived_draftungraded
Experimental context and source evidence
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/
Complete structured claim and evidence
DOHH hydroxylates deoxyhypusine-eIF5A to hypusine-eIF5A using its oxygen-activating diiron center.
DOHH → eIF5A1 with deoxyhypusine at residue 50 source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human DOHH structures and spectroscopy.
limitations
DOHH is a diiron enzyme, not a 2-oxoglutarate-dependent hydroxylase. 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 second enzyme completes the special modification.
primary_references
[dohh-2015] 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
tissue_or_cell_type
Not specified as a whole tissue; see experimental model.
L-Lysine: mechanism-first literature curation (2026-09-17) · lines 588–596
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human DOHH structures and spectroscopy. · source_derived_draft · unverified_draft
### dohh-eif5a-hypusine DOHH hydroxylates deoxyhypusine-eIF5A to hypusine-eIF5A using its oxygen-activating diiron center. Plain language: A second enzyme completes the special modification. Condition category: normal organism: Human tissue_or_cell_type: Not specified as a whole tissue; see experimental model. experimental_model: Human DOHH structures and spectroscopy. limitations: DOHH is a diiron enzyme, not a 2-oxoglutarate-dependent hydroxylase. This reaction modifies lysine already in a protein. It does not show that extra oral lysine increases the reaction or improves a clinical outcome. [dohh-2015] 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
Complete structured claim and evidence
Biochemical binding and structural experiments identify PLP as the human ODC coenzyme.
PLP → Human ornithine decarboxylase / ODC1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human and Leishmania ODC comparison; human inhibitor-bound structure.
limitations
Cofactor dependence does not establish that extra B6 raises polyamines in a replete person.
nutrient_topic
L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine
plain_language
The polyamine branch connects to vitamin B6.
primary_references
A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 1-amino-oxy-3-aminopropane. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17407445/ · DOI 10.1042/bj20070188
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 102–108
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human and Leishmania ODC comparison; human inhibitor-bound structure. · source_derived_draft · unverified_draft
## arg-odc-cofactor The polyamine branch connects to vitamin B6. Biochemical binding and structural experiments identify PLP as the human ODC coenzyme. Model: Human and Leishmania ODC comparison; human inhibitor-bound structure. Limitations: Cofactor dependence does not establish that extra B6 raises polyamines in a replete person. Evidence access: Primary abstract A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 1-amino-oxy-3-aminopropane. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17407445/ · DOI 10.1042/bj20070188
Complete structured claim and evidence
Human SRM uses putrescine as the amine acceptor for aminopropyl transfer from decarboxylated SAM.
Putrescine → Spermidine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
AMD1 decarboxylation generates the aminopropyl donor used in polyamine synthesis.
S-Adenosyl-L-methionine → Decarboxylated S-adenosylmethionine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human S-adenosylmethionine decarboxylase biochemical study.
limitations
Do not confuse aminopropyl donation with GAMT methyl transfer.
nutrient_topic
L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine
plain_language
SAM must be chemically changed before this branch uses it.
primary_references
Structural basis for putrescine activation of human S-adenosylmethionine decarboxylase. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19053272/ · DOI 10.1021/bi801732m
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 150–156
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human S-adenosylmethionine decarboxylase biochemical study. · source_derived_draft · unverified_draft
## arg-amd-reaction SAM must be chemically changed before this branch uses it. AMD1 decarboxylation generates the aminopropyl donor used in polyamine synthesis. Model: Human S-adenosylmethionine decarboxylase biochemical study. Limitations: Do not confuse aminopropyl donation with GAMT methyl transfer. Evidence access: Primary abstract Structural basis for putrescine activation of human S-adenosylmethionine decarboxylase. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19053272/ · DOI 10.1021/bi801732m
Complete structured claim and evidence
Putrescine stimulated human AMD1 autoprocessing and decarboxylation through a binding pocket separate from the active site.
Putrescine → Human S-adenosylmethionine decarboxylase / AMD1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human AMD1 structures, binding measurements and targeted mutants.
limitations
Feedback demonstrated at enzyme level; not a measured systemic methyl-donor drain.
nutrient_topic
L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine
plain_language
A pathway product helps activate production of the next branch’s donor.
primary_references
Structural basis for putrescine activation of human S-adenosylmethionine decarboxylase. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19053272/ · DOI 10.1021/bi801732m
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 142–148
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human AMD1 structures, binding measurements and targeted mutants. · source_derived_draft · unverified_draft
## arg-amd-feedback A pathway product helps activate production of the next branch’s donor. Putrescine stimulated human AMD1 autoprocessing and decarboxylation through a binding pocket separate from the active site. Model: Human AMD1 structures, binding measurements and targeted mutants. Limitations: Feedback demonstrated at enzyme level; not a measured systemic methyl-donor drain. Evidence access: Primary abstract Structural basis for putrescine activation of human S-adenosylmethionine decarboxylase. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19053272/ · DOI 10.1021/bi801732m
Complete structured claim and evidence
Human spermine-synthase substrate/product structures and mutagenesis support aminopropyl transfer to spermidine.
Spermidine → Spermine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The product-bound SMS structure supplied a mechanistic explanation for inhibition by methylthioadenosine.
5′-Methylthioadenosine → Human spermine synthase / SMS source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human SMS structural and biochemical study.
limitations
Product inhibition is not a measured dietary-arginine effect.
nutrient_topic
L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine
plain_language
A reaction product can slow its own production pathway.
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 166–172
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human SMS structural and biochemical study. · source_derived_draft · unverified_draft
## arg-sms-inhibition A reaction product can slow its own production pathway. The product-bound SMS structure supplied a mechanistic explanation for inhibition by methylthioadenosine. Model: Human SMS structural and biochemical study. Limitations: Product inhibition is not a measured dietary-arginine effect. 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
Complete structured claim and evidence
Human MAT2A formed S-adenosylmethionine before rapid triphosphate hydrolysis and product release in the kinetic study.
Human methionine adenosyltransferase 2A / MAT2A → S-Adenosyl-L-methionine source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/phosphorus-research/33656855.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1d45073f7187a06cfb9b2d630f94fa651239f0a9a5ae353b37d9af90750f2f38", "start_char": 0, "end_char": 1520, "text_sha256": "1d45073f7187a06cfb9b2d630f94fa651239f0a9a5ae353b37d9af90750f2f38"}
experimental_model
Human MAT2A kinetics, isotope exchange and inhibitor-bound crystallography
exposure
ATP/methionine reactions and PNPNP ligand complexes
limitations
Phosphoryl chemistry is not evidence that phosphate supplements boost methylation. Metal contacts were resolved with an experimental ATP-site ligand.
nutrient_topic
Phosphorus research collection; topical membership is not evidence of a direct dietary effect. · Phosphorus
organism
Human recombinant enzyme
plain_language
Making the methyl donor SAM is coupled to ATP-derived phosphate chemistry.
primary_references
[phosphorus-p33656855] Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. (2021). https://pubmed.ncbi.nlm.nih.gov/33656855/ DOI: 10.1021/acs.biochem.0c00998
tissue_or_cell_type
Purified MAT2A active site
Phosphorus: metabolism, signaling and nutrient connections (2026-09-17) · lines 633–644
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human MAT2A kinetics, isotope exchange and inhibitor-bound crystallography · source_derived_draft · unverified_draft
### phosphorus-mat-sam Human MAT2A formed S-adenosylmethionine before rapid triphosphate hydrolysis and product release in the kinetic study. Condition category: normal nutrient_topic: Phosphorus research collection; topical membership is not evidence of a direct dietary effect. plain_language: Making the methyl donor SAM is coupled to ATP-derived phosphate chemistry. organism: Human recombinant enzyme tissue_or_cell_type: Purified MAT2A active site experimental_model: Human MAT2A kinetics, isotope exchange and inhibitor-bound crystallography limitations: Phosphoryl chemistry is not evidence that phosphate supplements boost methylation. Metal contacts were resolved with an experimental ATP-site ligand. exposure: ATP/methionine reactions and PNPNP ligand complexes evidence_span: {"source_cache": "artifacts/phosphorus-research/33656855.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1d45073f7187a06cfb9b2d630f94fa651239f0a9a5ae353b37d9af90750f2f38", "start_char": 0, "end_char": 1520, "text_sha256": "1d45073f7187a06cfb9b2d630f94fa651239f0a9a5ae353b37d9af90750f2f38"} [phosphorus-p33656855] Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. (2021). https://pubmed.ncbi.nlm.nih.gov/33656855/ DOI: 10.1021/acs.biochem.0c00998
Complete structured claim and evidence
Purified recombinant human ARG2 catalyzes arginine hydrolysis to ornithine and urea.
Human arginase 2 / ARG2 → L-Arginine source_derived_draftungraded
Experimental context and source evidence
experimental_model
Recombinant human ARG2 expressed in E. coli and purified
exposure
Substrate/product kinetics
limitations
Primary experimental scope only; no human dietary threshold, clinical treatment rule, or universal metal substitution is established.
nutrient_topic
Manganese research collection; topical membership is not evidence of a direct dietary effect. · Manganese
organism
Homo sapiens protein
plain_language
ARG2 breaks arginine into ornithine and urea.
primary_references
[mn-enz-11370664] Expression, purification, and characterization of human type II arginase. (2001). https://pubmed.ncbi.nlm.nih.gov/11370664/ DOI: 10.1006/abbi.2001.2324
tissue_or_cell_type
Purified ARG2
Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 572–582
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human ARG2 expressed in E. coli and purified · source_derived_draft · unverified_draft
### mn-enz-arg2-hydrolysis Purified recombinant human ARG2 catalyzes arginine hydrolysis to ornithine and urea. Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: ARG2 breaks arginine into ornithine and urea. organism: Homo sapiens protein tissue_or_cell_type: Purified ARG2 experimental_model: Recombinant human ARG2 expressed in E. coli and purified limitations: Primary experimental scope only; no human dietary threshold, clinical treatment rule, or universal metal substitution is established. exposure: Substrate/product kinetics [mn-enz-11370664] Expression, purification, and characterization of human type II arginase. (2001). https://pubmed.ncbi.nlm.nih.gov/11370664/ DOI: 10.1006/abbi.2001.2324
Complete structured claim and evidence
The active truncated human ARG2 structure with a transition-state analogue supports a binuclear-manganese, metal-activated hydroxide mechanism for arginine hydrolysis.
Mn2+ → Human arginase 2 / ARG2 source_derived_draftungraded
Experimental context and source evidence
experimental_model
Crystal structure of active truncated human ARG2 with transition-state analogue
exposure
Boronic-acid inhibitor complex; 2.7-A structure
limitations
Structural consistency with the proposed mechanism; truncated active recombinant human ARG2 with inhibitor, not direct dietary manganese perturbation.
nutrient_topic
Manganese research collection; topical membership is not evidence of a direct dietary effect. · Manganese
organism
Homo sapiens protein
plain_language
Two manganese ions help ARG2 activate the water-derived attacking group.
primary_references
[mn-enz-12859189] Human arginase II: crystal structure and physiological role in male and female sexual arousal. (2003). https://pubmed.ncbi.nlm.nih.gov/12859189/ DOI: 10.1021/bi034340j
tissue_or_cell_type
Purified ARG2
Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 584–594
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structure of active truncated human ARG2 with transition-state analogue · source_derived_draft · unverified_draft
### mn-enz-arg2-metal-hydroxide The active truncated human ARG2 structure with a transition-state analogue supports a binuclear-manganese, metal-activated hydroxide mechanism for arginine hydrolysis. Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: Two manganese ions help ARG2 activate the water-derived attacking group. organism: Homo sapiens protein tissue_or_cell_type: Purified ARG2 experimental_model: Crystal structure of active truncated human ARG2 with transition-state analogue limitations: Structural consistency with the proposed mechanism; truncated active recombinant human ARG2 with inhibitor, not direct dietary manganese perturbation. exposure: Boronic-acid inhibitor complex; 2.7-A structure [mn-enz-12859189] Human arginase II: crystal structure and physiological role in male and female sexual arousal. (2003). https://pubmed.ncbi.nlm.nih.gov/12859189/ DOI: 10.1021/bi034340j
Complete structured claim and evidence
Purified human PPCS, PPCDC and bifunctional CoA synthase reconstituted CoA synthesis from phosphopantothenate in vitro.
4-Phosphopantothenate → Coenzyme A source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Provides the B5-derived CoA partner required by PDH, OGDH, BCKDH and OADH; simultaneous B1/B5 depletion was not tested.
evidence
[{"paper_key": "daugherty-2002-coa", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}]
experimental_model
Reconstituted human enzyme pathway.
limitations
Cross-pathway connection is biochemical integration, not a tested clinical supplementation interaction.
nutrient
Thiamine (vitamin B1) · Thiamine (vitamin B1)
nutrient_topic
Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)
organism
Homo sapiens
plain_language
Vitamin B5 supplies a separate carrier used after B1-dependent decarboxylation. The experiment starts with phosphorylated B5, so it does not test absorption or the first phosphorylation step.
primary_references
[daugherty-2002-coa] Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics (2002). https://pubmed.ncbi.nlm.nih.gov/11923312/ DOI: 10.1074/jbc.m201708200
tissue_or_cell_type
Purified recombinant enzymes
Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 731–743
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstituted human enzyme pathway. · source_derived_draft · unverified_draft
### b1-coa-b5-downstream-biosynthesis Purified human PPCS, PPCDC and bifunctional CoA synthase reconstituted CoA synthesis from phosphopantothenate in vitro. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin B5 supplies a separate carrier used after B1-dependent decarboxylation. The experiment starts with phosphorylated B5, so it does not test absorption or the first phosphorylation step. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzymes experimental_model: Reconstituted human enzyme pathway. limitations: Cross-pathway connection is biochemical integration, not a tested clinical supplementation interaction. evidence: [{"paper_key": "daugherty-2002-coa", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}] cross_nutrient: Provides the B5-derived CoA partner required by PDH, OGDH, BCKDH and OADH; simultaneous B1/B5 depletion was not tested. nutrient: Thiamine (vitamin B1) [daugherty-2002-coa] Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics (2002). https://pubmed.ncbi.nlm.nih.gov/11923312/ DOI: 10.1074/jbc.m201708200
Complete structured claim and evidence
Cryo-EM of active human complex II resolved FAD within SDHA and located the succinate-fumarate active site between its FAD-binding and capping domains.
SDHA → FAD source_derived_draftungraded
Experimental context and source evidence
evidence_spans
[{"source_bundle": "artifacts/riboflavin_metabolism_sources.json", "source_key": "PMC10161127", "locator": "XML .//body//p", "paragraph_index": 3, "char_start": 0, "char_end": 2164, "evidence_access": "full-text"}]
experimental_model
Human complex II purified from HEK293F cells, cryo-EM, EPR and succinate-quinone activity assays.
exposure
No nutrient intervention; structural or biochemical characterization.
limitations
Structure establishes location, not nutritional sensitivity.
nutrient_topic
Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)
organism
Homo sapiens
plain_language
The B2-derived cofactor sits in the catalytic SDHA part of complex II.
primary_references
[du-2023-human-complex-ii] Structure of the human respiratory complex II (2023). https://pubmed.ncbi.nlm.nih.gov/37098072/ DOI: 10.1073/pnas.2216713120
tissue_or_cell_type
HEK293F-derived purified complex II
Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 636–647
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human complex II purified from HEK293F cells, cryo-EM, EPR and succinate-quinone activity assays. · source_derived_draft · unverified_draft
### b2-met-human-sdha-fad Cryo-EM of active human complex II resolved FAD within SDHA and located the succinate-fumarate active site between its FAD-binding and capping domains. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The B2-derived cofactor sits in the catalytic SDHA part of complex II. organism: Homo sapiens tissue_or_cell_type: HEK293F-derived purified complex II experimental_model: Human complex II purified from HEK293F cells, cryo-EM, EPR and succinate-quinone activity assays. limitations: Structure establishes location, not nutritional sensitivity. exposure: No nutrient intervention; structural or biochemical characterization. evidence_spans: [{"source_bundle": "artifacts/riboflavin_metabolism_sources.json", "source_key": "PMC10161127", "locator": "XML .//body//p", "paragraph_index": 3, "char_start": 0, "char_end": 2164, "evidence_access": "full-text"}] [du-2023-human-complex-ii] Structure of the human respiratory complex II (2023). https://pubmed.ncbi.nlm.nih.gov/37098072/ DOI: 10.1073/pnas.2216713120
Complete structured claim and evidence
Adenosylcobalamin-loaded human MMUT converts (R)-methylmalonyl-CoA to succinyl-CoA in the coupled enzyme assay.
Human methylmalonyl-CoA mutase / MMUT → (R)-Methylmalonyl-CoA source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Full text Results; Figures 2-4; cofactor off-loading and MMUT activity Methods
experimental_model
Purified human proteins
exposure
AdoCbl-loaded MMUT and methylmalonyl-CoA; thiokinase-coupled readout
limitations
Product formation is a coupled assay; cellular net flux was not measured.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Purified human MMUT used activated B12 to make succinyl-CoA from the matching methylmalonyl-CoA epimer.
primary_references
[mascarenhas-2023-nanoassembly] Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair. (2023). https://pubmed.ncbi.nlm.nih.gov/37468522/ DOI: 10.1038/s41467-023-40077-4
tissue_or_cell_type
Purified protein assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1103–1115
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human proteins · source_derived_draft · unverified_draft
### mmut-isomerizes-r-methylmalonyl-coa Adenosylcobalamin-loaded human MMUT converts (R)-methylmalonyl-CoA to succinyl-CoA in the coupled enzyme assay. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Purified human MMUT used activated B12 to make succinyl-CoA from the matching methylmalonyl-CoA epimer. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: Product formation is a coupled assay; cellular net flux was not measured. exposure: AdoCbl-loaded MMUT and methylmalonyl-CoA; thiokinase-coupled readout cross_nutrient: false evidence_location: Full text Results; Figures 2-4; cofactor off-loading and MMUT activity Methods [mascarenhas-2023-nanoassembly] Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair. (2023). https://pubmed.ncbi.nlm.nih.gov/37468522/ DOI: 10.1038/s41467-023-40077-4
Complete structured claim and evidence
Spermidine increased the HADHA-attributed activity readout in mouse cardiac lysates from treated animals.
Spermidine → HADHA-attributed activity in lysate assay source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Spermidine-treated HFpEF mice showed improved fatty-acid-supported cardiac respiration.
Spermidine → Mouse cardiac fatty-acid oxidation capacity source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Spermidine improved the reported diastolic phenotype of mice in the HFpEF experiment.
Spermidine → Mouse cardiac diastolic impairment source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence

Availability and dependencies

Each situation shows the normal role first, then what the sources report under a specific condition. A shortfall in the diet, a fault in the machinery, and a low blood reading are kept separate because they are not the same thing.

Blocked synthesis interrupts starvation-induced autophagy

Condition: machinery_impairment · DFMO or ODC1 siRNA reduces polyamine synthesis.