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How NAD Precursors Work in the Body or what do I need to understand before taking a NAD supplement
Generated by ChatGPT (GPT-5 Thinking mini, OpenAI). Answer obtained August 10, 2025. Note: AI-generated content may contain inaccuracies; consult primary literature for clinical decisions.
Step 1 — Ingestion
• You swallow NR, NMN, or niacinamide.
• NAD⁺ itself is mostly broken down in the gut into smaller units before absorption.
Step 2 — Absorption
• NR: Taken up in the small intestine by nucleoside transporters.
• NMN: Likely broken down into NR before uptake in humans (still debated), though some evidence suggests a specific transporter exists in mice.
• Niacinamide: Readily absorbed via facilitated diffusion.
Step 3 — First-pass conversion
• In intestinal cells and liver, precursors enter the NAD salvage pathway:
• NR → NMN → NAD⁺
• NAM → NMN → NAD⁺
• Enzymes: NRK (nicotinamide riboside kinase) and NMNAT (nicotinamide mononucleotide adenylyltransferase) are key rate-limiting steps.
Step 4 — Distribution
• NAD⁺ made in the liver is not directly shipped out — instead, NAD precursors (like NAM) circulate and are taken up by other tissues to make their own NAD⁺.
Step 5 — Regulation & limits
• If intake is too high, excess NAM accumulates. This inhibits sirtuins and PARPs, counteracting benefits.
• Enzymes like CD38 constantly break down NAD⁺ — higher with age and inflammation, meaning older adults may “burn through” NAD⁺ faster.
• Cells balance NAD⁺ pools across the nucleus, cytosol, and mitochondria separately — boosting blood NAD⁺ doesn’t guarantee a big mitochondrial bump.
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Key takeaway for dosage:
• There’s a ceiling: above a certain point, enzymes and feedback loops turn extra NAD precursors into waste products or inhibitors.
• For most healthy adults in studies, 300–500 mg/day NR or NMN moves NAD⁺ significantly; beyond 1 g/day, gains flatten and side effects (like flushing or digestive upset) can increase.
Prompt:
What do we know about the biology of NAD taken as a supplement. By biology is meant does oral ingestion really result in improving what we know the molecule does. Also biology is replete with examples of just the right amount being critical and that suggests dosage matters
Response
NAD biology is tricky, because the molecule is central to metabolism but also because taking it as a supplement doesn’t work as cleanly as people often assume. Let’s break it down carefully.
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1. What NAD does in the body
• Core role: NAD⁺ (nicotinamide adenine dinucleotide) is a coenzyme that shuttles electrons in redox reactions — it’s essential for energy production (glycolysis, TCA cycle, oxidative phosphorylation).
• Other roles: It’s also a substrate for enzymes that regulate DNA repair (PARPs), gene expression (sirtuins), and cell signaling (CD38).
• Decline with age: Tissue NAD⁺ levels tend to drop with age and in certain diseases, which has spurred interest in supplements.
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2. The problem with taking NAD⁺ directly
• Poor absorption: NAD⁺ itself is too large and charged to cross cell membranes efficiently and is rapidly broken down in the gut.
• Blood stability: Even if some NAD⁺ gets absorbed, blood enzymes degrade it quickly into smaller molecules before it reaches cells intact.
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3. Why precursors are used instead
Most supplements aren’t pure NAD⁺ — they’re precursors that cells can convert into NAD⁺:
• Niacin (vitamin B3) — classic form, raises NAD⁺ but can cause flushing.
• Nicotinamide (NAM) — raises NAD⁺ but in high doses can inhibit sirtuins (feedback inhibition).
• Nicotinamide riboside (NR) — marketed for NAD⁺ boosting; shown to raise NAD⁺ in blood and some tissues in humans.
• Nicotinamide mononucleotide (NMN) — similar to NR, but one step closer to NAD⁺ in the biosynthetic pathway. Absorption route in humans is still debated.
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4. What the evidence says about oral supplementation
• Human trials: Small clinical studies show NR and NMN can raise blood NAD⁺ by ~20–60% within days to weeks.
• Tissue effects: Less clear — increases in muscle NAD⁺ are modest in healthy young adults, but more noticeable in older adults or those with metabolic issues.
• Functional benefits: Early human data suggest possible improvements in some measures (insulin sensitivity, vascular function), but effects are modest and not always reproducible.
• Animal vs human: Mice show bigger and more consistent benefits (lifespan extension, improved mitochondrial function) than humans so far.
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5. The dosage question — “just right” matters
Biology often follows a U-shaped curve:
• Too little NAD⁺ → impaired energy metabolism, DNA repair, resilience to stress.
• Too much NAD⁺ → potential issues:
• Sirtuin/PARP overactivation (could affect cell cycle or stress response).
• NAM accumulation from breakdown, which at high levels inhibits sirtuins.
• Possible support for growth of some cancer cells (since cancer often thrives on robust NAD⁺ metabolism).
• Most human trials use 250–1000 mg/day of NR or NMN and report it as safe for months to years — but long-term effects beyond that aren’t known.
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6. Key uncertainties
• Optimal target NAD⁺ level for different ages and conditions isn’t known.
• Which tissues benefit most from supplementation — blood NAD⁺ isn’t always a good proxy for brain, heart, or muscle.
• Whether long-term high-dose use has subtle downsides, especially in those without NAD⁺ deficiency.
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Bottom line
• Oral NAD⁺ itself doesn’t survive digestion well; precursors like NR and NMN do raise blood NAD⁺ in humans.
• There’s good biochemical evidence they work in principle, but the translation into large, lasting health gains in humans is still tentative.
• Dose likely matters a lot — both too little and too much could be counterproductive.
• At present, the strongest case for supplementation is in older adults or people with certain metabolic or mitochondrial disorders, not necessarily healthy young individuals.
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Human evolution and AI, a conversation with ChatGPT
Did Homo Sapiens undergo a near extinction event?
ChatGPT
The idea that around 800,000 years ago there was a near-catastrophic event reducing the population of Homo sapiens to about 1,000 individuals is a misunderstanding of two separate, though related, findings in paleoanthropology and genetics. Here’s a breakdown to clarify what’s known:1. Population Bottleneck (Misdated or Misattributed to Homo sapiens)
A study published in 2023 (Wang et al., Science) proposed a genetic bottleneck in ancient human ancestors that reduced the global population to as few as 1,280 breeding individuals, lasting for about 117,000 years, roughly between 930,000 and 813,000 years ago.
Key points:
• This event did not affect Homo sapiens, because our species didn’t yet exist. Homo sapiens evolved around 300,000 years ago.
• The bottleneck would have affected an ancestral species, likely Homo heidelbergensis or a similar ancestor to both Homo sapiens and Neanderthals.
• The bottleneck may explain a gap in the African and Eurasian fossil record and could be linked to environmental changes, such as major glaciation events.2. Environmental and Climatic Stress
Around 800,000 years ago, Earth experienced significant climatic transitions, including the so-called Mid-Pleistocene Transition, which led to longer, harsher glacial periods.
• These changes likely stressed populations of early humans and other species.
• Decreased rainfall and habitat loss in Africa could have contributed to population decline.An Important Clarification
• Homo sapiens was not alive 800,000 years ago, so no event at that time could have directly affected our species in terms of a near-extinction scenario.
• The small population size refers to ancestral populations, not modern humans.
• There is no archaeological or fossil evidence indicating Homo sapiens nearly went extinct at that point in history.Part 1: How Geneticists Model Ancient Population Bottlenecks
Geneticists use a field called population genomics to infer ancient events based on the genetic diversity of modern populations. Here’s how it works:
Step-by-Step of Genetic Modeling:
1. Collect modern genomes: From many diverse human populations.
2. Reconstruct ancestral lineages: Using models like coalescent theory, which tracks how DNA segments in modern humans trace back to common ancestors.
3. Simulate scenarios: Population sizes over time, migration, bottlenecks, and expansions.
4. Compare data: Match real genetic data to simulations to infer the most likely history.Key Study (2023):
• Researchers Wang et al. used AI-enhanced models on over 3,150 modern genomes.
• Their results suggest a genetic bottleneck in our ancestors around:
• 📍 930,000 to 813,000 years ago
• 📉 Population dropped to ~1,280 individuals
• 🕰️ Bottleneck lasted ~117,000 years
• Genetic diversity was drastically reduced, which explains:
• A long gap in the African fossil record (900,000–600,000 years ago)
• Possible divergence of lineages leading to Homo sapiens, Neanderthals, and DenisovansPart 2: Evolutionary Timeline Showing the Bottleneck
Here’s a simplified timeline of human evolution with the bottleneck marked:
🦴 2.5 Mya → First tools by Homo habilis
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🧠 2.0 Mya → Homo erectus appears
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🌍 1.5 Mya → Homo erectus spreads out of Africa
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⚠️ 930–813 kya → ⚠️ Genetic Bottleneck (~1,280 individuals)
↓ Possibly Homo heidelbergensis (common ancestor of sapiens & Neanderthals)
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🧬 ~700 kya → Neanderthal and Denisovan lineages split from sapiens lineage
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🏞️ ~600–400 kya → Homo heidelbergensis spreads in Africa & Europe
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🧑🔬 ~300 kya → Emergence of Homo sapiens in Africa
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🌍 70–50 kya → Out-of-Africa migration
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📜 12 kya → Start of agriculture and civilizationPosition of the Bottleneck:
• Occurred between Homo erectus and Homo sapiens
• Possibly at the transition from Homo erectus to Homo heidelbergensis
• May have helped drive speciation, eventually leading to modern humans⸻
🌍 Why the Bottleneck Happened (Hypotheses)
• 🌋 Volcanic activity (notably absent in this period but often suggested in other bottlenecks like Toba 74 kya)
• ❄️ Glaciation and climate change (the Mid-Pleistocene Transition brought harsher cycles)
• 🐘 Loss of megafauna and ecological shifts
• 🔄 Fragmented habitats and limited resources⸻
✅ Takeaway
The genetic bottleneck 800,000–900,000 years ago likely affected an ancestral species — not Homo sapiens directly — but it may have played a critical role in shaping the evolutionary trajectory that led to us.
Key to terminology
kya = thousand years ago
• For example, 300 kya means 300,000 years ago
• Mya = million years ago
• For example, 2 Mya means 2 million years agoSo:
• 100 kya = 100,000 years ago
• 1 Mya = 1,000,000 years agoPrompt: Didn’t another near extinction event occur?
A different near extinction event
a different and later bottleneck or survival episode — not the 800,000-year-old genetic bottleneck from earlier, but a hypothesized near-extinction event involving early Homo sapiens, often linked to:
📍 Southern Coastal South Africa (~130–70 kya)
Specifically: the Cape Coast region (e.g., Blombos Cave, Pinnacle Point)
✅ What’s the Hypothesis?
This idea comes from archaeological and genetic evidence suggesting that Homo sapiens may have gone through a dramatic population decline — possibly dropping to just a few thousand individuals — around 70,000 to 100,000 years ago.
A key part of the theory is that a small group survived along the southern coast of South Africa, sustained by a rich marine diet, including:
Shellfish (e.g., mussels, clams, limpets) Fish Seaweed Seabirds and marine mammals
🔬 Supporting Evidence
1. 🐚 Archaeological Sites with Shell Middens
Pinnacle Point, near Mossel Bay, has evidence of: Systematic shellfish harvesting Use of ochre pigments (symbolic behavior) Controlled fire use Stone tools showing innovation (blade-like tools)
2. 🧬 Genetic Evidence
Some studies (e.g., based on mitochondrial DNA) suggest a bottleneck as recent as 70–80 kya, possibly linked to: The Toba supervolcanic eruption (~74 kya), which may have caused global climate cooling Environmental stressors (e.g., drought in Africa)
3. 🌊 Ecological Haven Theory
The South African coast may have acted as a “refugium” — a safe haven where humans could survive tough inland conditions. The intertidal zone provided year-round, reliable calories — especially critical protein and fat — when inland food sources failed.
🧠 Why This Matters
This coastal survival theory helps explain:
How early Homo sapiens might have maintained a viable breeding population during climatic crises The rise of complex symbolic behavior and technological innovation in coastal southern Africa (possibly laying groundwork for modern cognition) Why modern humans may have spread out of Africa shortly afterward
Summary of the recent near extinction event 
Prompt: Is there a recent report on the biological change that the earlier near extinction might have brought about
Yes, recent research suggests that the severe population bottleneck experienced by our ancestral human population between approximately 930,000 and 813,000 years ago may have led to significant biological changes, potentially influencing the evolution of modern humans.
🧬 Chromosomal Changes and Speciation
One notable hypothesis is that this bottleneck coincided with major chromosomal rearrangements, such as the fusion of two ancestral chromosomes to form human chromosome 2. This fusion reduced the chromosome count from 48, as seen in chimpanzees, to 46 in humans. Such a change could have contributed to reproductive isolation from other hominin populations, facilitating the emergence of a new species. Additionally, rearrangements in the pseudoautosomal region 2 (PAR2) between the X and Y chromosomes may have occurred during this period, further influencing human evolution.
Source:
https://www.anthropology.net/p/the-genomic-timeline-of-becoming
🧠 Genetic Diversity and Cognitive Evolution
The bottleneck likely resulted in a significant loss of genetic diversity, with estimates suggesting a reduction of up to two-thirds. This loss may have increased the fixation of certain genetic traits, including those related to brain function. Some studies propose that interbreeding between two divergent hominin lineages around 300,000 years ago introduced genes associated with brain development into the Homo sapiens lineage. This genetic mixing could have played a crucial role in the cognitive advancements characteristic of modern humans.
Source accessed on 26 May 2025
🌍 Environmental Pressures and Evolutionary Impact
The bottleneck period coincided with significant climatic changes, including prolonged glaciations and droughts, which would have imposed substantial environmental pressures on hominin populations. These challenges may have driven natural selection, favoring traits that enhanced survival and adaptability. The combination of reduced population size, genetic drift, and environmental stressors likely contributed to the evolutionary trajectory leading to Homo sapiens.
Source provided by ChatGPT
Pivotal Event
In summary, the population bottleneck that occurred between 930,000 and 813,000 years ago appears to have been a pivotal event in human evolution, potentially leading to chromosomal changes, reduced genetic diversity, and the emergence of traits associated with modern humans. While further research is necessary to fully understand the implications, these findings offer valuable insights into the complex history of our species.
Prompt: Could AI drive human evolution by modeling and suggesting changes that could be made to the genome of Homo Sapiens using technologies such as CRISPR
Yes, AI could potentially drive or influence human evolution — but with critical ethical, technical, and societal boundaries. Here’s how that could unfold and what’s at stake:
🔬 How AI Could Drive Human Evolution via Genome Editing
1. AI in Genome Analysis & Editing
AI is already revolutionizing genomics in ways that set the stage for profound biological influence:
📊 Pattern recognition: AI can detect mutations linked to disease or traits across massive datasets. 🧬 Predictive modeling: Algorithms can simulate how genetic edits might affect protein structure, gene expression, or long-term health outcomes. 🧪 CRISPR guide design: AI tools like DeepCRISPR and CRISPR-Net help design more precise, less risky gene edits.
2. Theoretical Evolutionary Impact
If applied intentionally, AI-guided genome editing could:
🧠 Enhance cognition (e.g., improved memory or processing speed) 💪 Increase disease resistance or lifespan 👶 Prevent inherited disorders in embryos 🌍 Adapt humans to future environments (e.g., radiation or climate change)
Over generations, such changes could steer the evolutionary trajectory of Homo sapiens — a kind of guided evolution, replacing natural selection with technological design.
⚠️ Challenges & Ethical Dilemmas
🧩 1. Complexity of the Genome
The genome is highly interconnected: editing one gene can affect many traits (pleiotropy). Traits like intelligence, personality, or longevity are polygenic and context-dependent — hard to safely “optimize.”
🧬 2. Unintended Consequences
Off-target effects, immune reactions, and ecological disruption could arise from poorly understood edits. Gene drive technologies (for population-wide changes) carry even higher risks in humans.
⚖️ 3. Ethics of Human Enhancement
Germline editing (affecting future generations) is banned in many countries. Raises questions of: Consent (for unborn individuals) Equity (will only the rich afford enhancement?) Identity (what does it mean to be human?)
🧑🏫 4. Social and Evolutionary Risks
If AI-driven edits are misused (e.g., for eugenics), it could fracture societies or create selective human “subspecies.” Natural genetic diversity is key to resilience — too much editing could make populations more vulnerable to future change.
Future Scenarios 1 
Future Scenarios 2 Conclusion
AI has the power to inform, accelerate, and potentially direct aspects of human evolution through tools like CRISPR — but its role will depend heavily on:
Our understanding of complex traits Societal values and ethics International regulations
AI won’t “drive” evolution unless humanity chooses to give it that role. And if we do, that evolution might be faster — but also riskier and more divisive.
Visualization
AI assisted human evolution -
Memorial Day 2025
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Shame on us Americans.
We cannot connect the dots.
Our ancestors didn’t just speak of liberty but strived for the better angels among us. Even as we had slaves, we fought for their emancipation.At one point of time Tiennamen square sent a glimmer of what liberty meant when a sole protestor stood amongst the tanks. The authoritarian regime won the day. They have far advanced beyond America in mastering AI technology. Just flip open the journals of science in the cutting edge areas of science and you will see a preponderance of names of Chinese origin.
America however took pride in Diversity and Inclusion. This meant that the American team that wins the Math Olympiad is made of Americans of Chinese origin.
It was not America that was the magnet for the brain drain into the Crown Jewels of Learning and Research, but LIBERTY where the mind is free to explore without yielding fealty to any ideal or emperor or great statesman.
Today there is a Trojan Horse called the Big Beautiful Budget bill with a weapon of mass destruction included in a clause to neuter any intelligentsia left in contemporary America in the ranks of the Judiciary.
This is the revenge of the deplorables we are seeing today. The grift is being advertised as necessary and a sign of intelligence.
Americans though are still shielded from the consequences in terms of privations that follow the loss of liberty.
That unique brunt of the dagger of authoritarianism is manifesting itself not from Tiennamen square but from their compatriot authoritarian regime in Russia.
Ukrainians are sacrificing for the ideals of liberty and democracy today with a hijacked American government with a Trojan horse to blow up liberty in this land.
Roman Sheremeta, Associate Professor of Economics at Case Western Reserve University has a Facebook page detailing the Ukrainian struggle.
Here is one link of Trump’s confession. Visit his page to read the modern day chronicle
https://www.facebook.com/share/r/18tW42fYG1/?mibextid=wwXIfr
Professor of American history, Heather Cox Richardson, MIT faculty among her credentials does just like Professor Sheremeta, chronicle the takedown of democracy in the USA.
Please visit her Facebook page for the daily analysis of the events unfolding that share a grim forecast unless we speak up.
Here is a link to one such piece that speaks to the shutdown of the channels that provided transparency. It is akin to the thief knowingly destroying the evidence.
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Big Beautiful Cloak and dagger provision in Finance bill
Nix the judiciary and hide the tracks in a bill that will be hurried through on purely partisan lines
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Trump’s sanctions on ICC’s chief prosecutor have halted tribunal’s work, officials and lawyers say | PBS News
Staffers and allies of the ICC said the sanctions have made it increasingly difficult for the tribunal to conduct basic tasks, let alone seek justice for victims of war crimes or genocide.
— Read on www.pbs.org/newshour/world/trumps-sanctions-on-iccs-chief-prosecutor-have-halted-tribunals-work-officials-and-lawyers-say -
Liz Cheney’s advice to the Democratic Party
Central Message:
The Democratic Party needs to stop relying on donations and decorum and start bold, coordinated action to fight the authoritarian regime currently consolidating power in the U.S.
Main Criticisms:
Dems are acting like this is politics as usual, while fascism is consolidating control.
Constant fundraising emails feel tone-deaf amid constitutional collapse. The party is unprepared, reactive, and lacking strategy or urgency.
The GOP has executed a long-term plan; Dems are behind and playing defense. Polite speeches and PR aren’t enough — action is urgently needed.
Key Demands / Action Items:
Create an Independent Civilian-Powered Investigative Coalition Involve experts, veterans, journalists, and watchdog groups.
Document corruption and abuse in real time. Public hearings if Congress won’t act. Preserve evidence for future accountability.
Join the International Criminal Court Show commitment to law and human rights. Challenge the GOP to explain why they oppose international oversight. Invite ICC observers into the U.S.
Fund State-Level Resistance Infrastructure Support rapid-response legal teams, sanctuary networks, and security training.
Focus on resistance, not campaigning.
Build local power under a hijacked federal government.
Educate the Public on Rights and Resistance Launch mass public education campaigns. Provide legal kits, multilingual guides, and encrypted communication tools. Offer survival tools, not slogans.
Leverage International Media and Watchdogs Stop relying on U.S. media to tell the truth. Feed real stories to global outlets (e.g., BBC, Al Jazeera). Use independent platforms like Substack and Bluesky. Create a Digital Safe Haven for Whistleblowers and Defectors Provide encrypted, anonymous escape channels for insiders.
Embrace former MAGA supporters who defect. Focus on building numbers, not ideological purity.
Dismantle the Authoritarian Structure Learn from South Korea’s dismantling of dictatorship. Target aides, enablers, and architects of the regime — not just the leader.
Independently investigate those behind Project 2025 and other tools of oppression.
Final Warning:
Time is running out. The Democratic Party still has a chance to be on the right side of history — but only through bold, unapologetic action. The public is watching — and expects backbone, not fundraising emails.
ChatGPT produced this but also gave this warning
Instead of donating to democrats I thought I’ll pay to promote my point of view. I have nothing to sell and don’t need money for what I do. I tried to pay but it was rejected. Here is the rejection
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Prof of American History, Heather Cox Richardson analysis of US news, second week of April 2025
Core takeaway
The Trump administration is centralizing power, politicizing security, weaponizing data, and eroding legal safeguards, especially against immigrants—but potentially against all citizens. These moves mark a shift toward authoritarian governance under the pretense of efficiency, security, and patriotism.
Main Argument 1: Politicization of National Security
Trump fired General Timothy Haugh, head of CYBERCOM and NSA, allegedly on the advice of far-right figure Laura Loomer. Former Air Force Secretary Frank Kendall warns this is deeply dangerous, as these roles oversee critical surveillance and cyberattack capabilities that must remain nonpartisan. Replacing such officials with loyalists risks misuse of national security tools against Americans and undermines lawful safeguards.
Main Argument 2: Militarization and Loyalty Over Law
Trump appointed John “Razin” Caine as chairman of the Joint Chiefs of Staff, bypassing legal requirements for prior roles. The move was technically legal via presidential waiver but seen as a politicization of the military. Kendall: The military is now indisputably politicized.
Main Argument 3: Misuse of Data and Surveillance
Elon Musk’s DOGE (Department of Government Efficiency) claims to cut costs but is really embedding loyalists in agencies and harvesting Americans’ data, especially to target immigrants. ICE uses Palantir’s ICM database to find undocumented individuals using hyper-specific filters, and DOGE is sharing sensitive personal data across agencies. SSA added people to the “death master file”—a list used to terminate benefits—causing people, including children, to lose access to credit, banking, and legal status.
Main Argument 4: Undermining Legal Protections
IRS Commissioner resigned over a secret data-sharing deal with DHS, breaking long-standing promises not to use tax data for immigration enforcement. A “hackathon” between DOGE, Palantir, and IRS engineers is creating a centralized system to cross-reference IRS data with other federal databases for deportation efforts. Errors abound—including threats to citizens and legal residents, highlighting the dangers of automating deportations without proper oversight.
Main Argument 5: Lawlessness in Deportation and Rendition
The government illegally rendered Kilmar Abrego Garcia, a legal U.S. resident, to El Salvador despite court orders. The Supreme Court ruled unanimously that the U.S. must return him, but the administration is delaying and refusing to act, showing disregard for both courts and individual rights.
Main Argument 6: Dangerous Expansion of Executive Power
Trump signed a military memorandum to create a buffer zone along the southern border, essentially turning it into a military base. This would allow soldiers to detain migrants and positions Trump to potentially invoke the 1807 Insurrection Act for mass deportations using the military. Justice Sotomayor warned: If the administration can do this to noncitizens, it can do it to citizens—and Trump officials have suggested as much.
ChatGPT generated this from her post on Facebook
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The MAGA playbook
In 3 minutes you will be in a position to understand the past 4 months of the USA and what to expect in the next 4 years.
https://www.facebook.com/share/r/1AJ4JTRExj/?mibextid=wwXIfr
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America today, 31 March 2025
Oligarchy buys America 
Oligarch rules 
Immigration is turned upside down with disregard of due process 
Harvard faculty, 90 law professors draft this letter explaining the destruction
medium.com/philosophytoday/dont-jump-to-conclusions-5dad21162a5a-
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