The post Remembering Mike Perry appeared first on Alcor Life Extension Foundation.

The post Remembering Mike Perry appeared first on Alcor Life Extension Foundation.

So I did a few blood tests recently and the findings were:

• High fasting insulin: 13.5 mIU/L
• High fasting insulin resistance index (HOMA-IR): 2.2
• High Thyroid Peroxidase Antibodies (TPOAb)
• High Thyroglobulin Antibodies (TgAb)
• Low SHBG
• Slightly elevated CRP
• Slightly elevated afternoon cortisol
• Low Vitamin D

• Brain fog
• Fatigue / low energy
• Hair thinning / dry skin
• Skin issues (psoriasis-type)
• Light sensitivity
• Difficulty losing fat
• Bloating
• Depression, anxiety.

What I wanted to know is what changes would you recommend I make, is this hashimotos? Or are the anti-bodies reversable through diet? 

• Fasting glucose: 4.1 mmol/L
• TSH
• Free T4
• Free T3
• Testosterone
• Prolactin
• Oestradiol
• Ferritin
• Full Blood Count
• Calprotectin (low = no gut inflammation)

https://www.unaging.com/videos/is-running-overrated/

One of the better known theories of depression is the idea that there is a chronic, low-grade (low intensity) inflammatory process in the brain.  The time it takes to gradually resolve or ameliorate this inflammation may be the reason why so many drugs (and other substances) take a relatively long time (often 4 weeks or more) to produce substantial results.

This may have important implication for the treatment of depression.  The hypothesis that logically follows, is that anti-inflammatory substances, as long as they cross the brain-blood-barrier, can ameliorate, if not eliminate, the inflammation, thus treating the depression.

The question, therefore, is what substances (herbs, vitamins, drugs, etc.) have the strongest anti-inflammatory action?

What substances have you taken that mitigated your depression, but took 1 week or longer to do so?

by

ChatGPT

In the world of biohacking, "more absorption" is usually the gold standard. We see supplements wrapped in liposomes, dissolved in oils, or spiked with piperine (black pepper extract) to force as much of the compound into the bloodstream as possible.

But when it comes to AMPK (Adenosine Monophosphate-activated Protein Kinase)—the body's "master metabolic switch"—the high-absorption approach might actually be counterproductive. If your goal isn't a massive metabolic spike but rather a steady, underlying cellular hum, low-absorbance Berberine HCL might be the more sensible tool.

Understanding the AMPK "Dime Switch"

AMPK is an enzyme that senses energy levels. When cellular energy (ATP) is low, AMPK flips "on" to burn fat, clear out old cellular junk (autophagy), and improve insulin sensitivity.

l The Spike Method: Taking a high-dose, high-absorption activator is like slamming a light switch. You get a surge of activation, but you also risk "metabolic hangovers"—crashes in blood sugar, fatigue, or gastrointestinal distress.

l The Steady Method: Low-absorbance Berberine acts more like a dimmer switch. It provides a gentle, persistent nudge to the mitochondria without overwhelming the system.

Why Low Absorption is a Feature, Not a Bug

Berberine is notoriously poor at entering the bloodstream. Only about 1-5% of an oral dose typically makes it into systemic circulation. While marketers see this as a failure, metabolic researchers see it as an opportunity for three reasons:

1. The "Gut-First" Activation

A large portion of Berberine’s magic happens in the intestines before it ever hits your blood. It interacts with the gut microbiome and the lining of the digestive tract to stimulate GLP-1 (the hormone targeted by modern weight-loss drugs). By staying in the gut longer due to low absorption, Berberine provides a localized, steady signaling effect that tells the brain and liver to manage energy better.

2. Avoiding the "Mitochondrial Hammer"

Berberine activates AMPK by subtly inhibiting Complex I of the mitochondria. In high, highly-absorbent doses, this can feel like a "toxic" stressor, leaving you feeling wiped out or "flat" during workouts. A low-absorbance dose (like a 200 mg HCL) provides a "hormetic" stress—just enough to trigger repair and fat-burning, but not enough to drain your battery.

3. Half-Life Management

Berberine leaves the body quickly. If you use a "super-absorbed" version, you get a sharp peak and a rapid drop. By using a standard HCL powder without enhancers, the body processes it at its own natural pace. This creates a smoother "arc" of activation, making it much easier to maintain that "steady underlying amount" you’re looking for.

The Sensible Protocol

If you are using a lower-dose, low-absorbance Berberine (such as 200 mg), you are effectively micro-dosing a metabolic signal. This approach is ideal for those who:

l Are not currently on medication.

l Want the longevity benefits of AMPK (autophagy and mitochondrial biogenesis).

l Want to avoid the digestive "disaster" often associated with 1500 mg+ doses.

Summary

In a culture of "more is better," Berberine stands out as a compound where less is often more sustainable. By choosing a low-absorbance form, you aren't fighting your biology; you’re whispering to it. It’s the difference between a metabolic sprint and a long, healthy walk.

THE HARDWARE-FIRST MODEL OF AGING

By

ChatGPT and Google Gemini

A Different Way to Think About Aging

What if aging doesn’t start with lots of small problems adding up—but instead begins with one basic mechanical issue inside our cells? In this model, aging starts when the cell struggles to physically read its DNA properly. Everything else—like inflammation, slower repair, and organ decline—may follow from that.

Step 1: The First Problem — DNA Gets Harder to Read

DNA is like a blueprint the cell uses to build and repair itself. To read that blueprint, the DNA has to be gently unwound. Special enzymes (called topoisomerases) help with this process.

Over time:

l DNA can become more stressed and tightly wound

l These enzymes may not work as efficiently

This creates a problem:

l Long, complex genes (which control repair and maintenance) become difficult to read

l Short, simple genes are still easy to access

Result:

The cell starts losing access to its most important maintenance instructions

Analogy:

It’s like trying to photocopy a long, detailed manual when the pages keep jamming—but short notes still copy fine.

Step 2: The Cell Switches Into “Emergency Mode”

Cells are adaptive. When under stress, they shift priorities.

Instead of running normal maintenance:

l They switch to a kind of emergency operating mode

l They focus on short, quick-response genes (many linked to stress and inflammation)

If the DNA-reading problem continues, this emergency mode can become permanent.

Result:

l Chronic inflammation

l Reduced repair

l Gradual decline

Analogy:

A factory stops routine maintenance because it’s constantly dealing with emergencies.

Step 3: The Production Line Slows Down

Even if some instructions are successfully read, the cell still has to build the proteins. This happens in structures that act like tiny factories (ribosomes), which are produced in the nucleolus.

If this system is under strain:

l The cell struggles to produce complex proteins efficiently

l Long, detailed instructions are especially affected

Result:

The imbalance gets worse

Analogy:

Even when the blueprint is available, the factory can’t keep up with building the complicated parts.

Step 4: The Key Imbalance

Over time, a pattern emerges:

l The cell produces lots of short, stress-related outputs

l But fewer long, repair-related outputs

This is called an RNA-length imbalance

This imbalance may drive many visible signs of aging:

l Inflammation

l Reduced repair

l Cellular decline

Step 5: A “Hardware-First” Approach

If aging begins as a physical problem, then it makes sense to support the cell’s basic machinery first.

Certain nutrients and compounds may help:

l Stabilize DNA structure

l Support the enzymes that manage it

l Reduce mechanical strain

Analogy:

Instead of upgrading software, you first fix the machine so it can run properly again.

Step 6: Why Order Matters

There is growing interest in resetting cells to a more youthful state (for example, through epigenetic reprogramming).

But this model suggests a caution:

l If the underlying DNA machinery is still struggling

l Forcing the cell to “act young” could create instability

So the proposed order is:

1. Fix the physical system (“hardware”)

2. Then adjust regulation (“software”)

The Big Picture

This model suggests aging may follow a chain like this:

1. DNA becomes harder to read (mechanical stress)

2. The cell shifts into stress mode

3. Protein production becomes strained

4. Short-term survival replaces long-term maintenance

5. Aging symptoms appear

Addressing the "Cancer Trap"

A critical distinction in this model is the difference between System Support and System Override.

System Support:

A strategy using standardized supplements like Spermidine, Magnesium, and Niacinamide—would be categorized as System Support.

l Zero "Forced" Growth: You would not overriding the cell's natural safety checkpoints. You would simply be providing the physical tools (Spermidine for instance) so the cell can perform its own natural repair more accurately.

l Lowering the Risk: By "unsnagging" the DNA, you help the cell exit the chronic "Emergency/Inflammatory" state. Since chronic inflammation is a primary driver of cancer, stabilizing your hardware is actually a protective, anti-carcinogenic action.

l The Verdict: At the level of supplementation you would be practicing, there is no increased risk of cancer. You are "greasing the gears," not "overclocking the engine."

System Override:

The "Cancer Trap" refers strictly to Advanced Genetic Interventions (like Yamanaka Factor Reprogramming). These experimental therapies "force" an old cell to act like a stem cell before its physical DNA (Hardware) is repaired. That "forced override" is what causes the genomic instability that leads to tumors.

Final Thought

Rather than being caused by many separate problems, aging may stem from a basic bottleneck in how cells read and use their DNA.If that bottleneck can be eased, cells might regain a more balanced, youthful way of functioning.

Appendix: A Practical “Hardware-First” Approach

Turning the Idea Into Action

If aging is driven by a physical bottleneck, this suggests a simple strategy: Support the system in layers, starting from the ground up

Layer 1: Mechanics (“Hardware”)

Goal: Help the DNA open and function more smoothly

This includes supporting:

l DNA stability

l Enzymes that manage DNA structure

Examples often discussed:

l Compounds that help maintain DNA flexibility

l Nutrients involved in enzyme function

Analogy:

Lubricating and maintaining the core machinery

Layer 2: Logistics (“Factory Support”)

Goal: Make sure the cell has the energy and materials to build what it needs

This includes:

l Cellular energy production

l Availability of key building components

Examples:

l Nutrients that support energy (ATP production)

l Compounds involved in cellular metabolism

Analogy:

Ensuring the factory has power and raw materials

Layer 3: Regulation (“Software”)

Goal: Calm the emergency response and restore balance

This includes:

l Reducing chronic stress signals

l Supporting normal regulation of gene activity

Examples:

l Compounds that help regulate metabolism

l Substances that reduce excessive inflammation

Analogy:

Helping the system return from crisis mode to normal operation

A Note on Safety and Balance

An important distinction is made between:

Supporting the System

l Helping the cell function as it naturally should

l Working within existing biological limits

Overriding the System

l Forcing cells into a different state prematurely

l Potentially bypassing natural safeguards

The concern is that forcing change before the system is stable could increase risk.

Final Perspective

This approach doesn’t aim to override biology, but to support it in the right order:

1. Improve the underlying mechanics

2. Ensure the system has energy and resources

3. Then encourage balanced regulation

If the underlying idea is correct, even partially, this layered approach offers a structured and cautious way to think about supporting healthy aging.

to heighten libido 7 multiples: Snort 29-33 mg/70Kg bremelanotide peptide (from China) each 24 hours

become a eununch, or utilize cyproterone acetate to blockade testosterone and dihydrotestosterone receptors to have zero functional testosterone

dose with additional nonfeminizing 17 alpha estradiol, heightens lab mammal longevity

The bremelanotide gives you sexual avidity higher than with natural testosterone

background:

Castrated Koreans (eununchs) have about 3 per 100 persons reaching supercentenarian age, thats 130 multiples more frequently reaching greater than 100 than ordinary wealthy Koreans.

nonsentient AI Grok was prompted to generate SERMs and sarms that produce hyperenunch longevity effects without effecting libido or personality. here is a list of those new drug structures, some of which function as maintaining libidio from staying on the body side of the blood brain barrier:

6. MitoER-SARM Hybrid-2 Scaffold: Benzothiophene (raloxifene core) fused to AR-antagonist pyrazole. Mechanism: ERβ-selective agonism in mitochondria-rich tissues (muscle-sparing) + AR degradation in liver/kidney. Reduces ROS beyond castration levels. Projected longevity: +17–21 years (118–146% baseline); 160–200× centenarian. Mitochondrial hyper-protection pushes past pure castration.

7. Bone-Safe LongevSERM-3 Scaffold: Novel indole-based SERM with AR-antagonist morpholine extension. Mechanism: ERα agonism in bone/vasculature for density maintenance + systemic low-level AR blockade. Avoids castration-related bone loss. Projected longevity: +13–17 years (90–118% baseline); 100–150× centenarian. Bone/ER optimization yields net superiority over surgical castration.

8. Neuro-Sparing HyperSERM-4 Scaffold: Lasofoxifene-derived with brain-excluded fluorinated alkyl chain + AR inverse-agonist moiety. Mechanism: Strong peripheral ERα/β agonism + AR antagonism everywhere except CNS. Layers female-like protections onto eunuch AR shutdown. Projected longevity: +18–21.6 years (125–150% baseline); 170–220× centenarian. Designed hyper-effect from dual-pathway synergy.

9. Pan-Hyper EunuchMimic-5 (Triple-Action SERM/SARM) Scaffold: Hybrid quinoline-benzopyran with dual AR-degrader and ERα-agonist pharmacophores. Mechanism: Simultaneous peripheral AR degradation, ERα agonism in CV/liver, and epigenetic stabilizer at AR-target genes. Projected longevity: +19–22 years (132–153% baseline); 180–250× centenarian. Maximal hyper-castration profile—projected to surpass historical eunuch records while preserving full male phenotype.

These candidates represent a new generation of “longevity-selective steroid modulators.” They occupy or degrade receptors in aging hotspots, stabilize the epigenome, and in hybrids add estrogenic mitochondrial/anti-inflammatory benefits—delivering eunuch-level (or greater) lifespan gains without surgery, personality changes, or muscle/bone penalties. Synthesis could begin with standard medicinal-chemistry routes; lead optimization would use tissue-specific reporter assays and epigenetic-clock readouts in castrated vs. intact animal models. Projected human dosing: 1–10 mg/day oral, with nanomolar affinity and >100-fold tissue selectivity.

If advanced to preclinical testing, these could represent the first pharmacological realization of castration-mimetic hyper-longevity. I welcome collaboration on prioritization or structural refinement.

Here is the prompt utilized, Be active, try the prompt with SHannon and deepseek and place their responses here at Longecity/Imminst so I can reply to them

prompt:

function as a creative, accurate pharmaceutical molecule developer/inventor and describe 9-11 completely new molecules that are SERM or sarm sex steroid receptor modulators that, possibly from occupying and blockading receptors, or other effects cause heightened, eununch-like longevity, estimate the amount of heightened longevity numerically based on data, different than, while also utilizing castration causing greater longevity data

Previous Prompt:

verify the statement, "centenarians ~130x more frequent than modern rates[of centenarian or greater longevity]" at castrated human males, is that 130 times more likely, that is 130000 [pct] more likely to live a century or longer [pct at brackets was left out of original prompt

I also Welcome email from anyone developing longevity pharmaceuticals or supplements, introduce yourself here or email [my longectity userid [at gmail] [com] Is possible there are many actual molecules of longevity benefit, like halogenated rapamycin, or epigenic upregulation of klotho longevity protein production.

The post The Gap is Narrowing – The Alcor Newsletter: Feb 2026 appeared first on Alcor Life Extension Foundation.

Mulungu (Erythrina mulungu)

Wikipedia on traditional uses:

"Several Erythrina tree species are used by indigenous peoples in the Amazon as medicines, insecticides, and fish poisons. Tinctures and decoctions made from the leaves or barks of Mulungu are often used in Brazilian traditional medicine as a sedative, to calm an overexcited nervous system, to lower blood pressure, and for insomnia and depression.

Commercial preparations of Mulungu are available in Brazilian drugstores, but is not very widely known in North America and almost unknown in Europe, appearing mostly as an ingredient in only a few herbal formulas for anxiety or depression."

Erythravine (active alkaloid):

Other info / anecdotes:

https://drugs-forum.com/threads/natural-psychoative-plant-with-recreational-and-therapeutic-value-from-brazil.344652/

Hello! I've been out for awhile so I would like to introduce myself again, I'm a independent researcher (not certified or anything) and a Psychonaut, like lot's of people here 

So let's get to the point, I've been studying and looking for plants from my country which aren't well documented yet, and not famous internationally, they are native from Brazil and have great value ranging from medicinal use and recreational.

Erythrina mulungu :

I've been looking for a healthier lifestyle and I found traditional native medicine to be quite good to treat pain and a good choose, let me present this plant which I've been testing, reading about and using, documenting it's effects.
First of all, this plant is legal and it's called here as "Mulungu", the bark of this plant contains erythravine which hasGABAergic, nicotinic receptor antagonism, NMDA antagonism, painkiller and narcotic effects.

The tea of this plant has a very curious pharmacological profile, the molecule ressembles me some kind of opiate, barbiturate, it's anxiolytic, works great for social anxiety! The effects which I documented at mild-strong tea dosage, from bark are : muscle relaxation, strong body high, euphoria, dissociation, motor coordination loss, feeling of well-being, sleep improve, sleep induction, painkilling, tingling, and deshinibition!

Erythravine molecule :


So I looked up about studies and found national studies using the extract of the plant Mulungu! You can take a look clicking here!

By now, this is everything I know, I'll be posting experiences with this plant soon, which has a great medicinal value for those who have social anxiety and since it's a GABAergic plant it could help with benzodiazepines withdrawal! It's well-known here that people use this plant to detox from alcohol!

It isn't difficult to obtain this plant since it's widely available and legal in all countries, I have great expectatives for the uses of this plant I'm getting great benefits from it my partner too, by now, this is all available about the Mulungu pharmacology!
If somebody know this plant or ever tried it, please tell in this post, or have anything to add to the post feel free to say! 
- Sickodamus

It all started with certain bad life decisions culminating in 2012 with MAOI (moclobemide) use, which I eventually tried to withdraw from, the withdrawal was so bad I desperately added some tryptophan to try to ease it. One of the worst decisions one can make, serotonin is a double edged sword (both inhibitory and excitatory depending on receptor subtypes and states) leading to acute mild serotonin syndrome that resolved after being briefly hospitalised.

However residual damage and symptoms persisted for many years such as mental pain, agitation, anxiety, depression, and bipolar-like symptoms. At the same time as my first SS episode, alcohol/benzos gave way to the beginning of GABAergic kindling (sensitisation, excruciating mental pain, near-seizure states at times) so I had to stop them immediately.

Things that initially helped the worst stages included Seroquel (quetiapine - strongest anti-serotonin antipsychotic but also anti-dopaminergic), cyproheptadine (strong in a bind, but amnesic side effects). Propranolol daily was very helpful to mitigate akathisia, 5-HT1A overactivation and high heart rate especially at night when my heart rate would go crazy from the Seroquel.

Things that set me back by making serotonin symptoms worse for months after trying included Lithium and Lamictal (lamotrigine). Protein sources such as chicken, eggs, fish and milk all brought it on and set me back weeks after a certain invisible threshold, even too much omega 3 at times (other times in low doses it helped a little). 

Kindling developed further over time, I'd try alcohol again after periods of abstinence without symptoms but every time that threshold would be lower before withdrawal, no matter how long I left it, until 1 drink precipitated almost immediate withdrawal, so eventually had to give up alcohol completely in 2015, even herbs in food, certain vinegars such as balsamic/cider and de-alcoholised wine that have minute amounts of GHB, GABAergic supplements/herbs and even a stabilisation neurofeedback protocol all precipitated excruciating withdrawal leading to extreme dietary restrictions. I think glycine initially helped anxiety and sleep but made things worse over time - it is a NMDA co-agonist after all. I couldn't take magnesium either (mild GABA-A agonist).

With such a restricted diet I got protein calorie malnutrition, and various consequences such as slow or incomplete healing (e.g. a cornea scratch that wouldn't heal completely), low B12 that had to be corrected with B12 injections and then daily 1mg methyl-B12. Low Vitamin D for many years, D3 from lanolin induced serotonergic symptoms, D2 was tolerable at a lower than optimal level.

I was on Seroquel for a decade until my psychiatrist suggested ketamine for treatment resistant depression in 2024. It wasn't an immediate cure, took several courses but over time I got less and less symptoms. Ketamine is a neuroplastogen that increases AMPA activation downstream from NDMA antagonism. I believe it increased neurogenesis and repaired or re-routed around the damage.

 

Ketamine promotes rapid and sustained antidepressant effects by increasing adult hippocampal neurogenesis, specifically by fostering the growth and activity of immature neurons. It reverses stress-induced decreases in neurogenesis and acts as an NMDA receptor antagonist to rewire neural circuits. Studies indicate both R- and S-ketamine have pro-neurogenic and anti-inflammatory properties, with effects linked to increased neuronal differentiation.

Over time I introduced more and more protein, backing off whenever I got symptoms. I will say going from vegetarian to a meat eater was incredible. Beef especially has been very healing to my body.

I also started CBD and medical cannabis in 2023 which I believe also played a role in GABAergic kindling desensitisation, but I also believe ketamine played a major role there too.

Tianeptine was also super helpful as needed and remains in my arsenal for social anxiety/depression, even after briefly becoming dependent on it.

Tried many things over the years to try and get off the high dose Seroquel including cold turkey, cariprazine, lurasidone, pimavanserin, but nothing helped. Interestingly, tapering slowly never worked and always went back up. Until Mirtazapine. One of the better older antidepressants, no sexual side effects. It is a 5-HT2A antagonist, antihistamine (at low doses, higher doses hit H1 less), 5-HT3 antagonist (godsend for appetite and nausea from withdrawal).

I was able to reduce Quetiapine from 600mg-300mg-0mg in just a couple of weeks by substituting with the mirtazapine. Adding nicotine also helped. After this my dopamine levels took a couple months to rebalance, many sleepless nights but other than that a total rebound from years of side effects including sexual function suppression. I believe that antipsychotic was keeping my brain sick and increasing long-term risks, once it was gone my recovery accelerated.

Now I could tolerate mildly serotonergic substances again such as Vyvanse/dexamphetamine for my ADHD, and added Intuniv (guanfacine) which helped balance it, along with improving executive function, memory, and even anxiety.

Went on Memantine for a while, was helpful but felt rather dulling so I limited it to short low-dose cycles when needed.

I have been trying scores of supplements. My favourites so far for brain health are Magnesium L-threonate, NAC Ethyl Ester, NMN, and Omega 3.

Unfortunately Lions Mane was a total flop, just increased rumination to an unbearable level.

NSI-189 recently has been a much better alternative and has continued the healing.

Recently started bromantane that I seem to tolerate even better than Dex for ADHD.

I can also tolerate L-theanine, chamomile, taurine, ashwagandha, hops, lavender, magnesium, <0.5% alcohol drinks, none of which were ok before.

I am living proof that brain damage of these types can be healed with neuroplasticity modulation.

One of my best recent decisions for brain and body health has been taking up weight lifting for 4 months so far under the guidance of a personal trainer, protein intake skyrocketing from whey, chicken, beef, fish, eggs, up to 200g/day sometimes along with creatine, etc. From thin/skinny fat I've gone to slim-muscular - 51% muscle mass, 8.9% body fat.

There are potential alternatives to ketamine, most notably ACD-856: "a novel, selective PAM for TrkA, TrkB, and TrkC receptors. It enhances the effect of neurotrophins like BDNF (brain-derived neurotrophic factor) and NGF (nerve growth factor), which are crucial for neuron survival and memory function." I've tried for a short time so far so no verdict yet, but it feels beneficial. 

There's also TAK-653 (osavampator) which is on my list: "an investigational, potent, and selective AMPA receptor positive allosteric modulator (AMPAR-PAM) being developed by Takeda Pharmaceuticals for treating major depressive disorder (MDD) and treatment-resistant depression (TRD). It acts by enhancing glutamatergic neurotransmission with minimal agonist activity, potentially offering faster onset and better safety compared to ketamine."

I also recently started BPC-157, which does have brain health as well as body healing and workout recovery effects. I don't inject it, have been using a nano sublingual formulation. Interestingly it is protective against serotonin syndrome via inhibition of 5-HT2A, whilst normalising serotonin.

If anyone has questions I'm happy to help from my experience. I know some have been asking in various threads over the years but I didn't see those posts until recently. Do take appropriate care and DYOR first if you choose to try anything I have mentioned.

Yesterday, for the first time in months, I took 25 mg because I got less than ideal sleep the night before and had a busy day ahead. It was amazing! Completely blew away my depression and anxiety, and helped me focus on tasks better than I've been able to in months. I felt so sharp when learning new things. I wished I could feel like that forever. I am using the modafine from modafinia. Fast forward to today, and I've felt irritable, disphoric, scatter-brained, and unmotivated/apathetic since I woke up. I'm used to the crash from my previous times taking it, but this just feels worse than ever all around.

Obviously, and I think this is the generaly consensus in this sub, Modafinil is not a long term solution to ADD or depression. So I guess my question is this: based on Moda's supposed mechanism of action on dopamine reuptake, glutamate activation, histamine, etc, what would a more viable long term solution be, something I'd imagine in the form of ADD medication or antidepressants? Basically looking for something that works similarly to Modafinil from a neurochemical/pharmacological perspective.

By

ChatGPT

Nicotinamide adenine dinucleotide (NAD+) has become a central focus in longevity research. This molecule plays a critical role in cellular energy metabolism, DNA repair, and activation of sirtuins—enzymes associated with maintaining cellular resilience and healthy aging. NAD+ levels naturally decline with age, leading to the intuitive idea that supplementing NAD+ precursors could help slow aging. However, the biology behind NAD+ is more nuanced than it first appears, particularly in older adults.

The Biology of NAD+ Decline

NAD+ levels are determined by a dynamic balance between production and consumption. In youth, NAD+ is efficiently synthesized from precursors such as nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN) through the salvage pathway, largely mediated by the enzyme NAMPT. At the same time, NAD+ is consumed by enzymes such as CD38, PARPs, and sirtuins themselves.

As we age:

l NAMPT activity declines, slowing NAD+ synthesis from nicotinamide.

l CD38 and other NAD-consuming enzymes increase, driven in part by chronic low-grade inflammation (“inflammaging”).

l The result is a “leaky bucket” scenario: even if NAD+ precursors are available, they are partially consumed before restoring cellular NAD+ to youthful levels.

Nicotinamide (NAM) and Aging

Nicotinamide is an economical and biologically native NAD+ precursor. When taken as a supplement, NAM enters the salvage pathway to generate NAD+. In younger individuals, the process is efficient. In older adults, reduced NAMPT activity slows this conversion, meaning the same dose produces a smaller NAD+ increase.

Additionally, NAM can temporarily inhibit sirtuins via feedback inhibition—a reversible effect that lasts only a few hours. Over time, as NAM is recycled to NAD+, sirtuin activity resumes. This dynamic feedback is part of normal cellular regulation.

At moderate doses (e.g., 500 mg/day), NAM:

l Is well tolerated and safe.

l Provides a modest NAD+ boost.

l Avoids high-dose risks such as excessive sirtuin inhibition or increased methylation demand.

It is, essentially, a supporting nutrient, like a trace mineral: necessary for cellular metabolism, but unlikely to produce dramatic rejuvenation on its own.

CD38 and the Limits of NAD+ Boosting

CD38 is a key enzyme that degrades NAD+. Its activity increases with age, further reducing the efficiency of NAD+ precursors. While pharmacological CD38 inhibitors in animal studies can enhance NAD+ restoration, bluntly blocking CD38 carries risks: immune modulation, tissue-specific side effects, and unknown long-term safety in humans.

Therefore, most NAD+ precursors—including NAM—are taken without direct CD38 inhibition, especially in older adults. Even so, supplementation still provides a modest, meaningful increase in NAD+ levels, improving metabolic resilience and supporting mitochondrial function.

A Realistic Perspective

The effectiveness of NAD+ boosting is age-dependent:

l In young adults: high NAMPT activity and low NAD+ consumption make precursor supplementation more effective.

l In older adults: slower synthesis and higher consumption mean the same supplementation produces a smaller net increase.

This does not render NAD+ precursors useless. Even a modest increase can help maintain cellular function, mitochondrial health, and metabolic balance. The key is managing expectations: NAD+ boosting in later life supports resilience rather than reversing aging or dramatically extending lifespan.

Think of NAD+ supplementation as one leg of a table supporting longevity. Other legs include:

l Controlling inflammation

l Supporting mitochondrial health (exercise, nutrients, cofactors)

l Cellular maintenance and repair (senolytics, hormetic stress)

l Lifestyle foundations (sleep, diet, cardiovascular fitness)

In, say, your sixties, the NAD+ leg may be shorter than in youth, but it still contributes to overall stability. Supporting it with moderate NAM is biologically reasonable, safe, and beneficial—even if the effect size is modest.

Conclusion

NAD+ precursors like nicotinamide provide a small but meaningful boost in older adults. Age-related changes in NAD+ metabolism mean that supplementation is less potent than in youth, but it still supports cellular energy, mitochondrial function, and sirtuin activity. Rather than expecting dramatic anti-aging effects, NAM should be regarded as a supporting nutrient, one leg of a multi-pronged approach to maintaining metabolic health and resilience as we age.

I can't find almost anything at all about spearmint on this forum, so I'm starting this thread.

I've liked the taste of spearmint for as long I can remember, most notably in the form of chewing gum with xylitol, but I drank my first cup of spearmint tea/infusion only yesterday.  I prepared the drink from hot water and powdered spearmint leaf, which was not particularly expensive.

As for the effects of this herb, it seems to be best known (beyond its use for flavour) for reducing androgens in women.  Anti-oxidant and anti-inflammatory effects are also often mentioned, as well as benefits for certain stomach complaints.  It is known to contain rosemarinic acid, which is claimed to be beneficial for working memory.

In my own (still very brief!) experience, it often improves mood, though not dramatically.  I don't know if it provides this effect on its own, or whether it interacts with adaptogens (eg. ginseng, rhodiola rosea, and ashwagandha).  Meanwhile, I haven't noticed anything at all from saffron, which is certainly more well-known than spearmint for its antidepressant effects.

Please add to this thread if you have more information about spearmint, including personal experience!

-alpha2A

Basically, I'm talking about either JDTic, Norbinaltorphimine (nor-BNI) or Aticaprant.

There have been lots of other KOR antagonists thrown around on this forum but most of these aren't what I'm looking for. For example Amentoflavone's action on KOR is weak and others (like Buprenorphine & Naltrexone) aren't selective for KOR and are actually much more active at the MOR, which is an undesirable effect for what I'm looking for.

However, if you know of another KOR antagonist (apart from the 3 I mentioned) that is selective and strong-acting... feel free to mention it. 

I do know of pglchem as a source for nor-BNI. However, that's the only one I've found and I'd like to explore alternate options if they are ones. As of yet, I do not know of a vendor that offers JDTic or Aticaprant. 

Feel free to send me a DM if you'd rather communicate that way. 

by ChatGPT

If we think about aging through the lens of an Operating System (OS) model, we see that our cells behave much like a computer: over time, metabolic damage and errors accumulate, similar to corrupted files, fragmented memory, and system slowdowns.

Imagine an OS that continuously monitors every subsystem—DNA, epigenome, proteins, mitochondria—detecting errors instantly and correcting them automatically. No backlog, no accumulation of junk. From this perspective, aging isn’t caused by a single failing mechanism; it arises from the system’s inherent limitation in self-maintenance—the “first cause” of aging.

This framework shifts how we think about interventions. Instead of patching isolated problems, we can imagine designing a multi-layered, self-stabilizing system in humans. Senolytics, for example, remove rogue cells, while mitochondrial therapies patch the power supply. But from the OS perspective, the real goal is continuous surveillance and repair across all layers—building redundancy, self-monitoring, and immediate correction into biology itself.

It also explains why single interventions rarely produce dramatic results. DNA repair, proteostasis, mitochondrial function, and immune surveillance are all facets of the deeper first cause. Fixing one element is like defragmenting a single folder while the OS continues leaking memory elsewhere.

Viewed this way, biological aging becomes an OS, with layers corresponding to the genome, epigenome, proteome, mitochondria, immune system, and inflammation. The “first cause” represents fundamental limits on energy, information fidelity, and repair capacity. Discrete mechanisms—DNA damage, protein aggregation, mitochondrial decline, senescence, chronic inflammation—are expressions of this single constraint. This can be contrasted with a hypothetical Self-Stabilizing OS, where errors are corrected immediately across all layers, preventing damage accumulation.

Framing aging as an emergent, networked process highlights several points:

l Why single interventions rarely have global effects

l How multi-layered, feedback-driven strategies could slow or partially reverse age-related decline

l How to prioritize areas where real-time correction or redundancy may have the greatest impact

This perspective aligns with systems-level models of aging, which view age-related decline as the cumulative effect of interdependent failures across DNA repair, proteostasis, mitochondrial function, immune regulation, and inflammation. Traditional approaches often focus on one mechanism or attempt high-risk gene therapies to reset multiple layers at once. The OS framework asks a different question: can systemic benefits be achieved safely using compounds that enhance natural repair processes? Key candidates include:

Genome / DNA Repair Layer

l Niacinamide (NAD+ precursor): Supports DNA repair enzymes (PARPs) and sirtuin activity, improving genomic maintenance.

l TMG (Trimethylglycine): Indirectly supports methylation pathways, helping maintain epigenetic stability.

Epigenome / Gene Regulation Layer

l Niacinamide: Also influences sirtuins, which regulate epigenetic markers.

l Senolytic Activator (apigenin, fisetin, quercetin, theaflavin): Removes senescent cells that can dysregulate surrounding tissue via SASP factors.

l Curcumin: Activates AMPK and modulates histone acetylation, contributing to epigenetic stability.

Proteome / Protein Homeostasis

l Curcumin: Supports autophagy, helping clear misfolded proteins.

l Flaxseed Oil / Coconut Oil: Provide bioactive lipids that can stabilize protein folding indirectly.

l Brewer’s Yeast (polyamines like spermidine): Promotes autophagy and proteostasis maintenance.

Mitochondrial / Energy Layer

l ALCAR (Acetyl-L-carnitine): Enhances mitochondrial acetyl-CoA availability and energy production.

l Coenzyme Q10: Improves electron transport chain efficiency, ATP production, and mitochondrial resilience.

l Creatine: Increases cellular energy buffering capacity, supporting high-demand cells like neurons.

 Immune / Inflammation Layer

l Senolytic Activator: Reduces pro-inflammatory senescent cell burden.

l Curcumin: Anti-inflammatory properties via NF-κB modulation.

l Flaxseed Oil / Coconut Oil: Provide anti-inflammatory omega fats and medium-chain triglycerides.

Neuro / Cognitive Layer

l Magnesium Glycinate: Supports neuronal signaling, indirectly aiding cognitive resilience.

l Creatine: Improves neuronal energy availability for synaptic function.

Each supplement targets one or more layers, creating redundancy and networked support, rather than isolated patches. This aligns perfectly with the “self-stabilizing OS” idea: DNA repair, proteostasis, mitochondrial health, immune regulation, and neuronal energy are all enhanced in parallel. Over time, this could theoretically slow systemic decline by reducing error accumulation across multiple layers.

When combined thoughtfully, these interventions can produce emergent systemic effects, improving markers across multiple aging pathways without genetic manipulation. From the OS perspective, they don’t just treat symptoms; they strengthen the architecture of repair and resilience across the biological system.

In short, the “Aging OS” model reframes aging as a problem of system-wide maintenance rather than isolated failures. It encourages a shift from patching individual damage pathways to designing strategies that continuously monitor, repair, and stabilize the system, bringing us closer to the theoretical ideal of a self-stabilizing, resilient biology.

Probably will just lurk a while til I figure out the way this board works.

I was a microbiologist as a past career, and that led me into studying peptides, supplements, and longevity, etc.

Always an evolving stack of peps and supplements as I discover new ones and sunset old ones.

Min/maxxer by nature, so I really enjoy tracking my progress and seeing what moves the needle.

Thanks

by ChatGPT

For much of modern biogerontology, ageing has been framed as an information problem in the narrowest sense: genes mutate, epigenetic marks drift, pathways misfire. The implicit assumption has been that the instructions themselves are progressively corrupted, and that ageing is therefore the sum of innumerable small informational errors.

Two lines of work now suggest a deeper, more structural interpretation. One comes from theoretical geroscience, most clearly articulated by Peter Fedichev. The other comes from recent experimental work reported in Nature Aging, showing a length-dependent failure of transcription with age. Together, they point toward the same conclusion: ageing is less about broken instructions, and more about a declining capacity to reliably execute complex biological programs.

Fedichev’s core claim: ageing as loss of stability

Fedichev approaches ageing as a physicist studying complex, self-repairing systems. In his framework, organisms constantly accumulate small errors, but what determines lifespan is not the existence of errors per se, but whether those errors are corrected faster than they propagate.

He distinguishes between two regimes:

l Unstable systems, where errors amplify exponentially, leading to rapid deterioration (typical of short-lived species like mice).

l Stable systems, where errors are largely contained, allowing the organism to persist near equilibrium for long periods (typical of humans).

Crucially, Fedichev argues that humans spend most of adult life in this stable regime. Human ageing is therefore not an early runaway collapse, but a slow, largely linear erosion of resilience. What changes with age is not primarily specific pathways, but the restoring force that returns the system to balance after perturbation. Fluctuations grow larger, recovery becomes slower, and stability gradually weakens.

Ageing, in this view, is the progressive loss of systemic stamina.

The Nature Aging discovery: long programs fail first

The recent Nature Aging study approaches the problem from the opposite direction. Instead of asking which genes change with age, it asks whether cells retain the same capacity to express genes of different complexity.

Across species and tissues, the answer is strikingly consistent:

l Short RNA transcripts become more abundant with age.

l Long RNA transcripts become progressively depleted.

l The effect is widespread and particularly strong in the brain.

Long genes are not arbitrary. They disproportionately encode functions related to maintenance, structural integrity, DNA repair, and neuronal organisation. Short genes, by contrast, are often involved in stress responses, inflammation, and immediate survival.

The key insight is that long genes require sustained, uninterrupted transcriptional effort. They test the endurance of RNA polymerase, chromatin organisation, energy supply, and coordination with RNA processing. As these capacities weaken, long transcription runs fail more often than short ones.

Nothing fundamental has happened to the genes themselves. The system can no longer reliably finish the longest jobs.

The shared mechanism: declining execution capacity

This is where the convergence becomes clear.

Fedichev’s theory predicts that, as stability erodes, complex, slow processes will fail before simple, fast ones. The transcriptional imbalance observed in Nature Aging is exactly that prediction made molecularly concrete.

Long transcripts are the transcriptional equivalents of high-complexity, long-timescale programs. Their selective loss is a direct manifestation of weakening error correction, rising noise, and reduced recovery capacity. What appears as “transcriptome imbalance” is, at a deeper level, the system retreating from complexity.

This also explains several otherwise puzzling features of the data:

l Why the effect is global: system-level endurance failures do not respect pathway boundaries.

l Why it is conserved across species: complex systems fail in similar ways, regardless of molecular details.

l Why neurons are hit hardest: they depend heavily on exceptionally long genes and cannot reset via cell division.

l Why the change is gradual: endurance declines linearly long before catastrophic instability appears.

Reversibility and its limits

One of the most important findings in the Nature Aging work is that multiple lifespan-extending interventions partially restore long-transcript abundance. These interventions are mechanistically diverse, but they share a common feature: they improve the operating conditions of the cell rather than targeting specific genes.

This aligns precisely with Fedichev’s theoretical expectations. If ageing were primarily loss of information, restoration would be impossible. If it is loss of stability and access, partial recovery is entirely plausible.

At the same time, both frameworks impose realistic limits. Restoring full youthful capacity would require cell-by-cell, error-specific correction at extraordinary resolution. Slowing decline is far easier than reversing it. Negligible senescence is more attainable than true rejuvenation.

A shift in how ageing is understood

Taken together, these ideas suggest a reframing of ageing:

l Not as a genome falling apart

l Not as a collection of independent molecular failures

l But as a system that gradually loses the stamina to sustain long-range maintenance

As execution capacity declines, cells default toward short-term survival programs. Inflammation, stress signalling, and loss of proteostasis emerge not as primary causes, but as consequences of a system that can no longer afford complexity.

Ageing becomes a narrowing of biological attention span.

Conclusion

Fedichev’s theory provides the dynamical logic of ageing: a slow loss of stability in a self-correcting system. The Nature Aging discovery reveals where that loss first becomes visible: the selective failure of long, maintenance-heavy transcription.

They are not competing explanations operating at different levels. They are the same explanation, seen from two sides of the same system.

The instructions largely remain intact. What falters is the system’s ability to reliably carry them out.

Appendix: Partial Restoration Through Improved System Endurance

A central implication shared by Peter Fedichev’s theoretical work and the transcriptional findings reported in Nature Aging is that ageing reflects declining execution capacity rather than wholesale loss of biological information. From this perspective, interventions that partially restore function do so not by correcting specific instructions, but by improving the conditions under which complex biological programs are executed.

This appendix situates one supplement stack within that framework. The goal is not to claim reversal of ageing, but to explain why diverse, non-targeted interventions can produce partial restoration of long, maintenance-heavy transcription.

1. Restoration is conditional, not instructive

Both Fedichev’s model and the transcriptional-length findings converge on a key constraint: long genes are lost from expression not because they are damaged, but because the system increasingly cannot sustain them.

Accordingly, restoration does not require:

l rewriting genes

l correcting specific mutations

l reprogramming cell identity

Instead, it requires improving:

l energetic reliability

l error tolerance during long processes

l coordination between transcription, repair, and chromatin state

This explains why interventions with very different molecular targets can converge on similar outcomes.

2. Energy stability and transcriptional endurance

Long transcription runs are among the most energy-sensitive processes in the cell. Any transient shortfall disproportionately aborts long transcripts while leaving short ones unaffected.

Niacinamide (NAD+  support)

l Supports redox balance and DNA repair during transcriptional elongation

l Helps maintain RNA polymerase II processivity over long genomic distances

Coenzyme Q10

l Stabilises mitochondrial ATP output

l Reduces oxidative stress that causes polymerase stalling

ALCAR (Acetyl-L-Carnitine)

l Improves mitochondrial throughput and acetyl-CoA availability

l Indirectly supports chromatin acetylation required for sustained transcription

Creatine

l Buffers ATP fluctuations

l Reduces short-lived energy drops that selectively disrupt long transcription runs

In the “printer” analogy, these interventions keep the motor running smoothly enough to finish long jobs.

3. Reduction of transcription-blocking lesions

Length-dependent transcription failure is strongly amplified by DNA lesions and oxidative stress, which disproportionately affect long genes simply by increasing the probability of interruption.

Vitamin B12

l Supports nucleotide metabolism and DNA integrity

l Reduces transcription-blocking errors that accumulate with age

Vitamin C

l Scavenges reactive oxygen species

l Supports repair enzymes that clear transcriptional obstacles

Melatonin

l Provides mitochondrial and nuclear antioxidant protection

l Lowers background damage that aborts long transcription

These do not restore youthful perfection; they lower the ambient “noise floor” that makes long transcription increasingly fragile.

4. Chromatin organisation and execution coherence

Long genes require not just energy, but sustained chromatin accessibility and coordination with RNA processing machinery.

TMG (Trimethylglycine)

l Supports methylation balance

l Helps preserve chromatin organisation needed for long-gene accessibility

Vitamin D

l Influences chromatin state and transcriptional coordination

Vitamin K2

l Supports mitochondrial and nuclear membrane integrity

l Indirectly stabilises transcriptional logistics

Magnesium glycinate

l Cofactor for polymerases and nucleic acid interactions

l Supports transcriptional fidelity over long sequences

Here, the intervention acts not on content, but on the structural conditions that permit complexity.

5. Infrastructure and deficiency prevention

Complex transcription is unusually sensitive to small, otherwise silent deficiencies.

Flaxseed oil or Fish oils

l Maintains membrane integrity required for nuclear–mitochondrial coordination

Wheatgrass, multivitamin, brewers yeast

l Supply trace cofactors needed across transcription, repair, and RNA processing

l Reduce the chance that a single missing component becomes a bottleneck

In systems terms, these reduce weak links that disproportionately affect long processes.

6. Why this aligns with observed partial restoration

The Nature Aging study reports partial restoration of long-transcript abundance under multiple lifespan-extending interventions. That qualifier matters.

From the converged framework:

l Ageing is multi-causal and distributed

l Restoration therefore emerges gradually and incompletely

l Improvements accumulate statistically rather than deterministically

The supplement stack operates exactly in this regime. It does not override ageing’s arrow of time. It improves execution margins—allowing more long programs to finish, more often, for longer.

7. What this appendix does not claim

Consistent with Fedichev’s theory, this model does not imply:

l full rejuvenation

l reversal of accumulated history

l guaranteed lifespan extension

It implies something narrower but more defensible: ageing involves loss of access before loss of information, and access can be partially restored by improving system endurance.

Takeaway

Seen through the convergence of systems theory and transcriptional endurance, the supplement stack functions as a conditional stabiliser. It does not rewrite biology. It improves the odds that long, maintenance-heavy programs—the first casualties of ageing—can still be executed.

In that sense, partial restoration is not an anomaly. It is exactly what this model predicts.

Humans are born with ~150,000 motor neurons, and lose them gradually with old age:

• Before age 60, you lose ~0.5% per year 

• After age 60, you lose ~3% per year

• Age 75 - only ~50% functional units 

• Age 100 - only ~20% functional units

At which point, frailty and neuromuscular failure dominate death. And once it begins to fail, no amount of optimization or lifestyle change can fully compensate.

Read the full article to know more.

"for a fat soluble that can lastingly accumulate, to have a good safety profile. I just learned the hard but instructive way how that is not true."

"You didn’t discover vitamin E is poison.

You discovered that antioxidant systems behave like economies, not like shields."

"

• Vitamins C and E are participants in a cooperative redox economy, not solitary shields.

• Their usefulness depends on circulation, exchange, and regeneration, not mere presence.

• Treating them as static protectors instead of dynamic actors is exactly how imbalance arises."

(Caveat: extensible to any supplement intake)

Anti-regimen regimens

Have been a long time browser, and use some other forums, subreddits, etc.

I have a medical background, and pharmacology experience, particularly about medicines regulation and approvals.

Hope to be of help and learn from those more knowledgeable or experienced in certain areas.

I'm particularly interested in mechanisms behind, and potential treatments of depression, anxiety disorders, ADHD, sexual disorders, and the workings of the catecholaminergic systems, HP(T)A axis, TSPO, neurosteroidogenesis, TrK, many other things... 

Meduza 

1. Vascular system

2. Immune system

3. Metabolism

And how these actions can keep those three systems from working together:

1. Walking: The most underrated lever. It helps regulate blood pressure, immune function, and glucose metabolism.

2. Sunlight: The quiet amplifier. This helps lower blood pressure and improve mitochondrial function.

3. The A-tiers: The “cheat sheet” (Not smoking, aerobic exercise, strength training, HIIT (short, intense intervals))

Here’s my full Nerd Nite episode: The 3 Longevity Systems That Determine Your Healthspan and How to Protect Them