ID: h-ab3a0af5
Hypothesis
NAD+ Precursor Supplementation to Reverse Poly(ADP-ribose) Polymerase-Driven Metabolic Catastrophe
NAD+ Precursor Supplementation to Reverse Poly(ADP-ribose) Polymerase-Driven Metabolic Catastrophe.
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 4 support✗ 4 oppose
🧪 Overview
NAD+ Precursor Supplementation to Reverse Poly(ADP-ribose) Polymerase-Driven Metabolic Catastrophe
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["DNA Single-Strand Breaks<br/>Oxidative Stress in AD"]
B["PARP1 Hyperactivation<br/>PAR Polymer Synthesis"]
C["NAD+ Depletion<br/>40-60% Loss in AD"]
D["SIRT1 Inactivation<br/>Deacetylase Impaired"]
E["PGC1alpha Inactivation<br/>Mitochondrial Biogenesis Loss"]
F["Energy Failure<br/>Neuronal Death"]
G["PARP1 Inhibitor<br/>Olaparib/Veliparib"]
A --> B
B --> C
C --> D
D --> E
E --> F
G -.->|"blocks"| B
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7⚖️ Evidence
⚖️ Evidence Matrix4 supports4 contradicts
Supports
Postmortem AD hippocampus shows 60-70% reduction in NAD+ concentration with corresponding PARP1 hyperactivation
Supports
NMN administration in 5xFAD mice restores cerebral NAD+ levels, improves mitochondrial function, and reduces amyloid plaque burden
Supports
Human trials of NR in older adults demonstrate safe NAD+ boosting and improvements in mitochondrial biomarkers in blood
Supports
SIRT3 deacetylase activity declines in AD brain, leading to hyperacetylated SOD2 and increased oxidative stress
Contradicts
NAD+ repletion in aged humans shows peripheral effects but unclear brain benefits - no direct CNS NAD+ measurement
Contradicts
PARP1 knockout mice show no protection against AD-like pathology - genetic deletion does not prevent amyloid deposition in APP/PS1 mice
Contradicts
PARP1 as primary NAD+ consumer is disputed - relative contributions of PARP1, SIRT1, SIRT2, CD38 vary by cell type
Contradicts
NMN supplementation studies use supraphysiological doses - mouse studies require doses unlikely achievable in humans
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — PARP1
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for PARP1, SIRT1/3, NAD+ from GTEx v10.
💉 Clinical Trials
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for PARP1, SIRT1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF C57BL/6J mice with chronic low-dose doxorubicin-induced PARP1 activation (10 μg/kg/week for 8 weeks) receive oral nicotinamide riboside (NR) supplementation at 400 mg/kg/day for 8 weeks, THEN hepat | Hepatic NAD+ levels ≥2.5 nmol/mg protein, representing ≥50% restoration toward baseline | — no observation — | pending | 0.65 |
| IF NR supplementation (400 mg/kg/day for 8 weeks) is given to the same PARP1-hyperactive mice, THEN fasting blood glucose will decrease by ≥25% (to ≤140 mg/dL) and insulin sensitivity (assessed by HOM | Fasting blood glucose ≤140 mg/dL and HOMA-IR reduction of ≥30% | — no observation — | pending | 0.55 |
🔮 Falsifiable Predictions (2)
pendingconf 65%
IF C57BL/6J mice with chronic low-dose doxorubicin-induced PARP1 activation (10 μg/kg/week for 8 weeks) receive oral nicotinamide riboside (NR) supplementation at 400 mg/kg/day for 8 weeks, THEN hepatic NAD+ concentrations will increase by ≥50% (to ≥2.5 nmol/mg protein) relative to vehicle-treated P
Predicted outcome: Hepatic NAD+ levels ≥2.5 nmol/mg protein, representing ≥50% restoration toward baseline
Falsification: Hepatic NAD+ remains <2.0 nmol/mg protein (no significant difference from PARP1-activated vehicle group) after NR supplementation, with p-value ≥0.05 in two-tailed t-test
pendingconf 55%
IF NR supplementation (400 mg/kg/day for 8 weeks) is given to the same PARP1-hyperactive mice, THEN fasting blood glucose will decrease by ≥25% (to ≤140 mg/dL) and insulin sensitivity (assessed by HOMA-IR) will improve by ≥30% relative to vehicle-treated PARP1-activated controls.
Predicted outcome: Fasting blood glucose ≤140 mg/dL and HOMA-IR reduction of ≥30%
Falsification: No significant improvement in fasting glucose or HOMA-IR (change <20%) despite NAD+ elevation; any worsening of metabolic parameters (glucose increase >10%); p-value ≥0.05 for all comparisons
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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