#81

### Does carnosine lower 8‑oxoguanine (8‑oxoG / 8‑oxo‑dG)?

Yes—in every model tested so far, raising tissue carnosine pushes 8‑oxo‑dG (the classic marker of oxidative DNA/RNA damage) downward.
The evidence base is still pre‑clinical, but it is internally consistent across cell culture, multiple rodent tissues and several stress paradigms:

Model Carnosine protocol Δ 8‑oxoG result Notes
tBHP‑stressed human oral & keratinocyte cultures 10 mM carnosine for 24 h Immunofluorescent 8‑oxoG ↓ ≈ 60 %; γ‑H2AX co‑reduction Linked to Nrf2/HO‑1 activation (ResearchGate)
Rat intracerebral‑haemorrhage brain (peri‑hematoma) 1 g kg⁻¹ i.p., single dose 8‑oxo‑dG immunostaining ↓ ~50 % at 72 h Also cut ROS, MDA, 3‑nitrotyrosine (PubMed )
Al₂O₃‑nanoparticle hepatotoxicity / testis stress (rat) 100 mg kg⁻¹ day⁻¹ i.p. × 4 wk Serum 8‑oxo‑dG halved vs toxin‑only; liver & testis protected Parallel fall in lipid peroxidation, MPO, XO (Imrpress Articles)

Magnitude: In most rodent organs carnosine cuts 8‑oxo‑dG by 30 – 60 %. That is on par with high‑dose N‑acetyl‑cysteine and stronger than vitamin C/E in the same models.

#### Mechanistic reasons it works

Step in 8‑oxo‑G pathway How carnosine interferes
Fenton chemistry (Cu²⁺/Fe²⁺ + H₂O₂ → •OH) The imidazole ring chelates Cu²⁺/Fe²⁺, throttling •OH production.
Radical propagation Scavenges •OH, O₂•⁻ directly; traps lipid‑alkoxyl and carbon‑centred radicals.
Secondary carbonyl wave (HNE, MG) Forms stable Michael adducts, stopping aldehyde‑DNA cross‑links that amplify 8‑oxo‑dG generation.
Antioxidant signalling Up‑regulates Nrf2 → HO‑1, SOD, GPx (shown in oral mucosa and brain).

Because carnosine is a dipeptide, it also buffers pH and shields histone lysines from glyco‑oxidative modifications, indirectly easing oxidative load on the genome.

#### Human data: promising but still thin

  • Small pilot RCTs (1–2 g day⁻¹) have confirmed rises in RBC carnosine and falls in advanced glycation end‑products, but urinary 8‑oxo‑dG has not yet been formally reported.
  • Ongoing trials (e.g., ClinicalTrials.gov NCT02686996) include 8‑oxo‑dG among secondary outcomes; first read‑outs are expected 2025–2026.

The key translational hurdle is serum carnosinase‑1 (CN1), which clears free carnosine in minutes. Strategies under investigation:

  • High‑dose pulsing (≥1 g twice‑daily)
  • Carnosinase‑resistant analogues (anserine, carcinine, “carnosinol”)
  • Co‑administration of thiols (e.g., NAC) or boronic dipeptidomimetics that partially inhibit CN1

### How carnosine compares with metformin / berberine for 8‑oxo‑dG

Compound Primary driver of 8‑oxo‑dG reduction Typical drop in rodent 8‑oxo‑dG Human evidence
Carnosine Direct metal chelation + radical/carbonyl scavenging 30 – 60 % Awaiting trials
Metformin (1–2 g d⁻¹) ↓ mitochondrial ROS via complex‑I modulation; ↓ glucose 15 – 30 % Small decreases in PBMC & urine in T2D cohorts
Berberine (≈1 g d⁻¹) AMPK activation → ↓ glucotoxic ROS; mild carbonyl trap 10 – 25 % One pilot reported urinary 8‑oxo‑dG −18 % in 4 wk

So carnosine is chemically the strongest direct shield, but metformin/berberine partly compensate by lowering upstream ROS drivers (hyperglycaemia, mitochondrial leak).

### Practical take‑aways

  1. Yes, carnosine can meaningfully lower 8‑oxo‑dG—at least in animals and cells.
  2. Dosing matters: effects emerge at tissue levels ≥5 mM; that translates to ~1–2 g oral in humans plus a way to outrun carnosinase.
  3. Combo logic: stacking carnosine with metformin or berberine attacks both the ROS and the DNA end‑products.
  4. Watch biomarkers: monitor urinary or plasma 8‑oxo‑dG alongside fructosamine/AGEs to see the full redox‑glycation picture.

Large placebo‑controlled human trials are still needed to confirm that the robust 8‑oxo‑dG drops seen in rats translate into people—and to show whether that ultimately matters for age‑related disease risk.

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