#530

Chinese preprint: Bmal1-Mediated Circadian–Ferroptosis Crosstalk Drives Neuronal Vulnerability after Mtbi

Traumatic brain injury (TBI) induces direct mechanical injury and secondary injury processes, among which ferroptosis, a regulated and iron-dependent form of cell death, has emerged as a key mechanism. Circadian clock disruption is also commonly described in TBI, especially mild TBI (mTBI) patients, and is reported to exacerbate pathological outcomes of TBI. However, the crosstalk between circadian clock dysfunction and ferroptosis in mTBI remains unclear. Using a mouse mTBI model, disrupted expression of core circadian clock regulators BMAL1, CLOCK, and PER2 was observed, accompanied by iron accumulation, blood-brain barrier (BBB) leakage, and neuronal damage. Ferroptosis inhibitors, melatonin (MLT) and liproxstatin-1 (Lip-1), alleviated mTBI-induced weight loss and neurological dysfunction. In contrast to MLT, Lip-1 failed to rescue body temperature rhythmicity, although both agents modulated circadian clock at the molecular level. Mechanistically, the Bmal1 downregulation sensitized HT-22 neurons to RSL3-induced ferroptosis in vitro by exacerbating oxidative stress and iron overload. Collectively, these findings demonstrated an asymmetric crosstalk, in which circadian clock disruption promotes ferroptosis, and inhibition of ferroptosis feeds back to modulate clock gene expression without restoring behavioral rhythms. This circadian–ferroptosis axis may represent a novel and promising target for therapeutic intervention in post-TBI neuroprotection.

#531

Sorry, I should have pointed it out… it showed that Maypro Industries is a key distributor of micro melatonin… I’d contact them and ask if they know where you can buy it, or if they sell to individuals (I doubt it but if you don’t ask, you don’t get :slight_smile:

To contact them:

Their phone is also at the bottom of that page.

1 Like
#532

Melatonin alleviates sodium sulfite-induced osteoporosis in mice via suppression of the ferroptosis pathway 2025

Sodium sulfite (SS) is a common food additive that is widely absorbed and distributed throughout the body, but its excessive intake has been linked to adverse health effects. Here, we investigate the impact of chronic SS exposure on bone tissue and the underlying mechanisms. Using a mouse model, we demonstrate that prolonged SS exposure induces significant bone loss, which correlates with alterations in ferroptosis-related markers. In vitro, SS exposure activates ferroptosis, which is characterized by elevated reactive oxygen species levels and impaired osteogenic differentiation in MC3T3 cells. Notably, melatonin, a potent endogenous antioxidant, mitigates SS-induced oxidative stress, inhibits ferroptosis, restores osteoblast function, and alleviates bone loss in mice. These findings highlight ferroptosis as a critical contributor to SS-induced osteoporosis and identify melatonin as a promising therapeutic agent for its prevention and treatment.

#533

O3: “what effect does sodium sulphite have on mitochondria”

Bottom line: sodium sulfite undermines mitochondrial energy production by blocking electron flow, collapsing the proton gradient, opening the permeability-transition pore and promoting ROS formation. Organisms cope by oxidising it to sulfate, but when that capacity is exceeded—or genetically absent—mitochondrial failure and cell death follow.

Hence the question arises “is it ferroptosis specifically or just protecting mitochondria more generally”.

I would guess the latter, but am too busy to look at the paper to see if I am right or not.

#534

Sorry that it took me that long to thank for such a detailed and as usual, informative response.
Thank you!!!

1 Like
#535

Exogenous melatonin alleviates premature ovarian failure by regulating granulosa cell autophagy 2025

Premature ovarian failure (POF) is a disease closely related to the apoptosis of granulosa cells (GCs) in the follicle. In this study, exogenous melatonin (Mel) was used to interfere with POF model mice, so as to provide reference for Mel prevention and treatment of POF. Mel could promote estrogen secretion and improve ovarian physiological function in mice. In GCs, mitochondrial membrane potential increases and ATP content increases, LC3/LC3-LL and Beclin1 expression increases, p62 expression decreases, which promoted the occurrence of autophagy. Intersecting target screening, GO and KEGG enrichment analysis of Mel and POF revealed that estrogen receptor 1 (ESR1) was the most compatible target for Mel action; meanwhile, Mel had a high enrichment value in the PI3K-AKT-mTOR pathway. It was detected that Mel could increase the expression of ESR1 and inhibit the phosphorylation levels of PI3K, AKT, and mTOR to promote autophagy and reduce apoptosis of GCs.

#536

O3:

Below is a cleaned, readable transcript (condensed for clarity), followed by a succinct summary and an evidence‑focused critique.

Tidied transcript (condensed & edited for clarity)

Notes: I’ve removed fillers, corrected obvious transcription errors (e.g., “ampophilic”→amphiphilic, “autorine”→autocrine, “supercosismatic”→suprachiasmatic), and grouped related points. The flow follows the video.

0:00–2:40 • Melatonin basics, distribution, and “light vs. dark”

  • Melatonin affects many organs: brain, retina, skin, liver, kidney, thyroid, thymus, muscle, and reproductive organs.
  • It’s present in many body fluids (amniotic fluid, breast milk, CSF, synovial fluid, saliva, urine, feces).
  • As an amphiphilic molecule it can cross barriers like the blood–brain barrier, placenta, and cell membranes.
  • Across the lifespan: very low in infants <3 months, peaks around ages 1–3, then declines ≈10–15% per decade; very low in older age and linked to mitochondrial dysfunction.
  • Framing: vitamin D as a “nutrient of light” and melatonin as a “nutrient of dark.” Adequate darkness is essential for sleep benefits.

2:40–5:40 • Physiologic roles; plants; mitochondria

  • Proposed roles: reproductive regulation, hormone synthesis, immune activation, UV protection, antioxidant/cytoprotective effects, aging, hematopoiesis, cardiovascular support.
  • Plants also produce melatonin (“phytomelatonin”) with overlapping functions (circadian regulation, germination, antioxidant activity).
  • Mitochondria: site of ATP and ROS generation; take up circulating (pineal) melatonin and may synthesize melatonin locally (non‑releasable, auto/paracrine actions). Melatonin concentrates in mitochondria and up‑regulates antioxidant enzymes (e.g., superoxide dismutase, glutathione reductase).

5:40–9:55 • Mitochondrial uptake; gut melatonin; microbiome

  • Uptake via MT1/MT2 receptors and receptor‑independent diffusion.
  • The GI tract is a major extra‑pineal source (reported much higher local concentrations than pineal output), acting locally.
  • In the gut, melatonin is said to: rebalance microbiota (↑beneficial/↓pathogenic), restore barrier integrity (↑tight junctions), reduce oxidative stress (↑antioxidant enzymes), and reduce inflammation (↓pro‑inflammatory cytokines).
  • Systemically: ↓stress hormones (corticosteroids, norepinephrine), ↓inflammation, and improved glucose homeostasis.

9:55–12:40 • Circadian disruption feedback loop

  • Normal: nighttime melatonin spike → anti‑inflammatory, antioxidant effects in gut; gut cells/bacteria produce extra‑pineal melatonin → feedback to pineal.
  • With chronodisruption (light at night, shift work, alcohol, etc.): attenuated spike → lower blood melatonin, impaired gut effects, disrupted feedback, more inflammation/oxidation risk.

12:40–16:40 • Inflammation, glucose, cognition; kynurenine pathway

  • Parallel inflammatory mechanisms in brain/periphery link ↑ROS and inflammation to insulin resistance and ↓melatonin; melatonin supplementation is presented as restorative.
  • Kynurenine pathway: ≈95% of tryptophan metabolism goes here to make NAD⁺; inflammation (↑IDO) diverts tryptophan away from serotonin/melatonin → ↑neurotoxic quinolinic acid; low B6 worsens this. Exercise shifts toward the serotonin–melatonin pathway.

16:40–20:25 • Cardiometabolic & timing with MTNR1B variant

  • Cardiovascular claims: melatonin helps regulate HR/BP, reduces reperfusion injury via antioxidant and anti‑apoptotic effects.
  • Glucose rhythm involves MT1/MT2 signaling under SCN control, independent of feeding.
  • MTNR1B variant: associated with higher fasting glucose/T2D and amplified melatonin signaling. Elevated melatonin during eating may impair glucose tolerance; caution with early‑morning labs or dosing; suggests time‑restricted feeding away from high melatonin windows.

20:25–22:00 • Cancer

  • Based on Warburg effect, the talk suggests daytime melatonin for cancer, co‑administered with chemotherapy to reduce toxicity.

22:00–27:30 • Fertility, pregnancy, infancy, pediatrics

  • IVF: melatonin reportedly improves oocyte quality and pregnancy rates; combo with myo‑inositol cited.
  • Pregnancy: maternal melatonin rises, crosses placenta; fetal melatonin receptors are widespread; breast milk has a day–night melatonin rhythm; breastfeeding in darkness is encouraged.
  • Pediatrics: short‑term studies (often in ASD/ADHD + insomnia) show melatonin is generally well tolerated; accidental pediatric gummy ingestions increased during the pandemic.
  • Puberty: limited human data; three small studies found no difference in puberty timing; one 2023 study linked higher melatonin to constitutional delay in boys. Presenter advises caution with peripubertal kids and proposes alternatives (e.g., 5‑HTP, B6, magnesium, L‑theanine/GABA).

27:30–31:10 • Perimenopause/menopause and male fertility

  • Perimenopause: high rates of short sleep; melatonin’s temperature‑lowering effect may aid sleep and vasomotor symptoms.
  • Estrogen–melatonin relationship is mixed; concurrent use considered acceptable.
  • Males: melatonin may reduce oxidative stress/apoptosis and normalize testosterone via improved testicular function.

31:10–33:40 • Aging, pineal calcification

  • Pineal gland calcifies with age (“inflammaging”); associations with neurologic conditions are noted. Speculation that melatonin might help reverse calcification.

33:40–35:55 • Testing patterns & light

  • Examples of salivary melatonin profiles: evening light suppression, shift worker with inverted curve, teen with delayed phase; suggests morning light therapy to advance phase.

35:55–38:05 • Product quality; phytomelatonin

  • Cites variability in OTC melatonin content and potential contaminants; recommends professional‑grade sources.
  • Claims phytomelatonin (plant‑derived) has higher ORAC (antioxidant capacity) and may act like a natural sustained‑release form; foods rich in phytomelatonin are not practical sources for pharmacologic dosing.

38:05–45:00 • Dosing, indications, timing, side effects

  • Typical nightly human production estimated around ~0.3 mg (speaker also mentions 3–6 mg elsewhere when discussing totals across 24h; dosing guidance generally exceeds physiologic levels).
  • Dosing ranges presented from literature across conditions (jet lag, insomnia, analgesia, neurologic disease, COVID, cancer, etc.); emphasis on lowest effective dose for shortest duration.
  • Immediate‑release 30–120 min before bed for sleep onset; sustained‑release for maintenance (often 0.3–3–6 mg). Start low (1–2 mg) and titrate.
  • Phase shifting: earlier afternoon/early evening dosing advances the clock; late‑night/early‑morning light can delay it. Avoid light after DLMO (dim‑light melatonin onset).
  • Side effects are usually mild and dose‑related (grogginess, headache, vivid dreams, GI upset). Safety margin described as wide; no evidence that exogenous melatonin suppresses endogenous production; no rebound insomnia on discontinuation in cited studies.

45:00–48:29 • Factors lowering melatonin & non‑melatonin supports

  • Blue light, alcohol near bedtime, seasonality, stress/cortisol, caffeine, some meds (e.g., beta‑blockers, NSAIDs) can reduce melatonin.
  • If avoiding melatonin: support the serotonin→melatonin pathway (tryptophan/5‑HTP, B‑vitamins—especially P‑5‑P/B6, iron if deficient, vitamin D), and prioritize exercise.

Summary (key takeaways)

  • Melatonin is presented as a system‑wide modulator (sleep, circadian timing, antioxidant/anti‑inflammatory actions, metabolism, reproduction, cardiovascular and brain health).
  • The mitochondria and gut are emphasized as major sites of melatonin action/production; healthy melatonin signaling is framed as crucial for mitochondrial redox balance and gut barrier/microbiome health.
  • Light/dark hygiene is central: daylight supports vitamin D; darkness supports melatonin; evening light suppresses/delays DLMO.
  • Metabolism: circadian melatonin/glucose interplay (MT1/MT2; SCN control); MTNR1B variant may worsen glucose control if eating when melatonin is high → consider timing meals away from late evenings/very early mornings.
  • Kynurenine pathway shifts tryptophan away from serotonin/melatonin under inflammation; B6 and exercise may counter‑shift.
  • Use cases discussed: insomnia, jet lag, analgesia, fertility/IVF, perimenopausal sleep/vasomotor symptoms, adjunct in cardiometabolic and neurologic conditions; cancer adjunct use proposed (including daytime dosing).
  • Dosing: start low, prefer immediate‑release for onset and sustained‑release for maintenance; avoid light after DLMO; monitor side effects.
  • Safety: generally well tolerated; pediatric use often in ASD/ADHD with insomnia; caution around puberty (limited data) and product quality; consider professional‑grade products.
  • Alternatives/adjuncts: light therapy, sleep hygiene, timing of meals, 5‑HTP/B‑vitamins/magnesium, and exercise.

Critique (strengths, gaps, and cautions)

What’s well‑grounded or reasonable

  • Light at night suppresses/delays melatonin: robust human data support minimizing evening light (especially blue‑enriched) and using morning light to advance circadian phase.
  • Immediate vs sustained‑release for sleep onset vs maintenance is clinically sensible and consistent with pharmacokinetics (short half‑life).
  • Product variability in OTC melatonin and reports of contaminants have been documented; recommending reputable sources is prudent.
  • Pediatric accidental ingestions rose during the pandemic; emphasizing safe storage is appropriate.
  • MTNR1B variant and impaired glucose tolerance with evening eating: supported by multiple studies; counseling on meal timing for sensitive individuals is reasonable (though genotyping isn’t always necessary—general advice to avoid late‑night eating often suffices).

Where the evidence is promising but limited or preliminary

  • Mitochondrial melatonin synthesis/localization: much of the mechanistic work is from cell/animal models; direct confirmation of effects and dosing translation in humans remains limited.
  • Gut microbiome modulation by melatonin: preclinical and small human studies exist, but the magnitude and clinical relevance across conditions need larger RCTs.
  • IVF/fertility: small trials suggest improved oocyte quality and possibly pregnancy rates, but effect sizes and optimal dosing/timing are not firmly established; “50% improvement” likely reflects relative changes in small cohorts and shouldn’t be generalized without context.
  • Neurodegenerative/psychiatric and cardioprotection claims: plausible mechanistic rationale and some early data, but routine use as disease‑modifying therapy isn’t established.

Statements that need stronger qualification or could mislead

  • “Nutrient of dark/light” framing is memorable but risks implying melatonin is a dietary essential. It’s an endogenous hormone/indoleamine; supplements can help with timing/symptoms but are not a replacement for proper light hygiene.
  • Physiologic production amounts: the talk mentions ~0.3 mg/day at one point and “3–6 mg” elsewhere; most estimates of endogenous nightly production are far below common supplement doses. This matters when comparing “physiologic” versus “pharmacologic” dosing and potential side effects.
  • “LD₅₀ is infinity” (i.e., no lethal dose): this oversimplifies safety. While toxicity is low and overdoses are rarely dangerous, side effects, drug interactions (e.g., CYP1A2 substrates/inhibitors), and daytime sedation are real considerations, especially at high doses or in older adults.
  • Daytime melatonin for cancer and high‑dose regimens (10–50+ mg): these are not standard of care; evidence is heterogeneous and should be handled within oncology care plans to avoid interactions with trials or supportive meds.
  • Phytomelatonin superiority & ORAC: ORAC is an in vitro metric with limited translational relevance; claims that phytomelatonin is categorically superior or inherently “sustained‑release” are speculative/marketing‑leaning. Quality control matters more than plant vs synthetic origin.
  • Pineal calcification reversal with melatonin: presented as a possibility; current evidence is associative, not proof that supplementation reverses calcification or alters clinical outcomes.
  • Puberty effects: human data are sparse and mixed. Advising caution in peripubertal youth is reasonable; framing should emphasize uncertainty rather than imply established harm.

Practical nuance that would strengthen the talk

  • Clear contraindications/interactions (e.g., anticoagulants, antiepileptics, immunomodulators), driving/operating risks if taken late.
  • Emphasize behavioral sleep interventions (consistent schedule, stimulus control, caffeine/alcohol timing) as first‑line, with melatonin mainly for circadian issues and select insomnia cases.
  • For glucose: advise everyone (not just MTNR1B carriers) to avoid late eating and pre‑bed snacks; consider the impact of shift work and tailor melatonin/light timing carefully.
  • Encourage trial discontinuations after sleep stabilizes to see if endogenous rhythms carry forward, rather than indefinite use.

If you want, I can:

  • Export a full cleaned transcript to a downloadable document, or
  • Build a one‑page dosing & timing cheat‑sheet (with onset vs maintenance, phase‑shift windows, and a light‑hygiene checklist).
    Tell me which you’d prefer.
#537

My view on this is that it misses the key link between mtDNA, splicing and aging/development and also does not look at the different levels of melatonin in CSF and serum as well as not looking at real high doses. Otherwise, however, it is quite a good video.

An interesting thought is that animal experiments with melatonin give an LD50 of infinity. However, that is not really true as if you were hit by a ton of melatonin you would be as dead as being hit by a ton of lead.

1 Like
#538

Austrian paper: Oral supplementation of melatonin attenuates the onset of alcohol-related liver disease 2025

Small dose: 50 ng/kg BW/day

Impairments of intestinal barrier function in small intestine in ethanol-fed mice were significantly attenuated in ethanol-fed mice treated with melatonin being associated with lower NOx and higher phosphorylation levels of AMPK.
Supplementation of “dietary” doses of melatonin dampens the development of ALD.
Melatonin attenuates alcohol-induced small intestinal barrier dysfunction.
Protective role of melatonin is related to alterations of AMPK activity.

#539

At lunch today I took 56mg of Fe, 3 g of pantethine and 1.2 g of DHM combined with 300mg of melatonin before I had 2 pints to drink of bitter. I intend drinking more today. The Fe is for two reasons a) I am mildly anemic and need some more Fe and want to do so when my digestion system is more diulted by water, when I have not drunk alcohol for 2 days my body probably reduces water levels by 2-3kg some of which is in the intestines. Hence taking Iron when drinking avoids any potential constipation as a result of the iron supplementation. b) Drinking alcohol tends to hit iron and copper levels,

The rest is to reduce the harm mainly from acetaldehyde (ethanal). This is 3.6mg / kg.

#540

This is for you, John. At least one doctor doesn’t think alcohol is all that bad.

1 Like
#541

Personally I think it is best to have a few days without alcohol.

Here’s a structured response with a tidy transcript, summary, novelty identification, and critique.

Tidy Transcript

Intro & Question

  • Opens by asking: Is drinking alcohol daily actually good for you?
  • Clarifies he’s not advocating heavy drinking, but questioning whether daily moderate drinking might not be harmful.
  • Personally a rare drinker, but intrigued by anecdotal patterns he sees in his work.

Case Example – 93-Year-Old Patient

  • Recently saw a hospital patient aged 93 who looked exceptionally youthful (~65).
  • Asked for his “secret.” Patient said: “I drink a couple of vodkas every single evening — it keeps me sane.”
  • Doctor did not advise him to stop, given apparent good health.

Repeated Observations

  • Frequently meets sprightly patients over 85–90 with few medications, good mobility, and sharpness.
  • Many report having a daily cocktail.
  • Mentions Queen Elizabeth II’s daily gin-based drink as another example.

Evidence & Research Context

  • Notes that research on moderate alcohol use is equivocal:

    • Moderate drinking (~2 drinks/day) sometimes associated with benefits, sometimes with harm.
    • Heavy drinking clearly harmful.

  • Questions whether these healthy older drinkers are healthy because of alcohol or simply healthy people who happen to drink.

Personal Perspective

  • Values personal clinical observation highly — sometimes over conflicting or agenda-driven research.
  • Wonders if what he sees is a “chicken and egg” scenario.
  • Notes blue zone cultures (especially Mediterranean) often have daily wine consumption.
  • Rarely hears daily beer drinkers reporting similar longevity, possibly due to calories and metabolic downsides.

Conclusion

  • Not planning to start daily drinking himself but open to discussion.
  • Encourages viewers to think independently, avoid over-medicalization, and aim for natural long-term health.

Summary

The speaker, Dr. Sil Dand, reflects on a recurring pattern in his clinical experience: many exceptionally healthy nonagenarians report daily moderate alcohol consumption, often wine, cocktails, or spirits (rarely beer). A recent standout example was a vibrant 93-year-old patient attributing his vitality to nightly vodkas. While acknowledging research on alcohol is mixed and heavy use is harmful, he suggests that moderate daily drinking might not be detrimental — and may even correlate with well-being in some populations. He emphasizes the value of direct clinical observation alongside (and sometimes over) conflicting research literature.

Novelty Identification

  • Novel element:

    • The presentation is not based on new research but on the speaker’s longitudinal, personal clinical observation over many years in hospital practice.
    • The novelty lies in framing anecdotal geriatric patient interviews as a repeated, consistent finding — linking vibrant longevity with moderate daily alcohol intake.
    • The discussion positions personal clinical pattern recognition as potentially more trustworthy than population-level studies when evidence is conflicted.
    • Suggests possible cultural parallels with Mediterranean “blue zone” drinking patterns.

Critique

Strengths

  • Engaging and relatable storytelling (93-year-old case, Queen Elizabeth reference).
  • Highlights the conflict between epidemiological research and individual observational patterns.
  • Raises a valid question: is moderate daily alcohol causative, neutral, or simply correlated with better baseline health?
  • Acknowledges heavy drinking harms and does not promote excess.

Limitations

  • Entirely anecdotal — no controlled data or statistical analysis.
  • Selection bias likely: patients reaching extreme old age and in hospital but still functional may be exceptional cases not representative of the population.
  • Does not address reverse causation: healthier individuals may tolerate alcohol without harm, rather than alcohol causing their health.
  • No consideration of confounders: diet, exercise, genetics, socioeconomic status, and social engagement may be stronger drivers.
  • Omits recent meta-analyses showing even low alcohol intake may slightly increase certain cancer risks.
  • Mediterranean and blue zone references are broad generalizations; causality remains speculative.

Overall Viewpoint
The talk is valuable as an anecdotal counterpoint to anti-alcohol narratives but lacks the rigor to support policy or personal health recommendations. At best, it supports the hypothesis that moderate alcohol is not universally harmful and may coexist with longevity in certain individuals or cultures. At worst, it risks reinforcing a health myth if interpreted as causative without considering confounding factors.

If you want, I can also cross-reference this with the latest meta-analyses on alcohol and all-cause mortality to see whether his anecdotes align with current high-quality evidence. That would put his observations in a sharper scientific context.

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#542

Looking at the broader issue. Many people who end up as supercentenarians are drinkers, but not necessarily heavy drinkers.

Enjoying life is almost certainly part of being more healthy. Alcohol can assist in this in relatively moderate quantities.

Personally, however, I think it is worth not drinking for a few days between binges to enable your body to adjust.