#222

A lot of functional tests like exercise and reaction time are practice related.

The key issue I look at is the function of the genome. That is a dimension orthogonal to practice.

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#223

You are supposed to take in around a total of 10-20,000 pg total (30-40k if you smoke) and then once you downregulate you stop taking it except for monthly maintenance micro-dose. You probably took in 60,000pg. Taking too much gdf11 can be just as bad as too little.

GDF11 dose instructions

#224

The dose makes the poison. I would consider DNP at doses much lower than those traditionally used for weight loss.It may extend lifespan in mice: Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity - PubMed

Low doses of DNP have hormetic effects that may be beneficial for some diseases:

The positive effects above are generally seen at doses far lower (roughly 10-100 times lower) than those that result in noticeable weight loss.

I would actually like to see DNP tested in the ITP.

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#225

It was – didn’t work, any thoughts?

Published May 2024:

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#226

Thanks. I didn’t know DNP had already been tested by the ITP. The results are disappointing. I notice that in the ITP study they used at least 5 times higher dose than the dose that was used in the earlier study that found extension of median lifespan. So it’s possible the dose used in the ITP study was too high, but I’m not sure. I haven’t researched this in detail.

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#227

Paul, I read through Steve Perry’s information and Turnbuckle’s information quite some time ago (more than once) and found none of what they said to be very compelling at all. I even watched Perry in his RAADFest 2022 GDF11 Presentaion. My thoughts about Perry always brought to mind the term “snake oil salesman.” However, I do still have interest in epitalon. So, post your thoughts when you have time, whether good or bad. Thanks.

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#228

Hi Jay

I carefully tracked my biometrics every day and blood work quarterly and never found the improvements he proclaimed. My sense is that GDF-11 was a wild goose chase and not the blood factor that is controlling aging. I did get a nice spreadsheet out of the experience which I keep up to this day over 5 years later.
It would be quite informative to know the cause of his death. He was taking klotho as well at the time.

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#229

I think we can all agree that Perry died way too young, so something either went horribly wrong or he was incredibly unlucky.

I remember him talking about how the dosing on GDF-11 was very difficult to get right and a little bit too much could have very negative effects. I wonder if this is what did him in.

In the end, Im not touching GDF-11 with a ten foot pole until more data comes out in favor of it.

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#230

In the end, Im not touching GDF-11 with a ten foot pole

Much of the hype around GDF11 was based around papers that have been called into serious question. See Elevated GDF11 Is a Risk Factor for Age-Related Frailty and Disease in Humans. That review was from 2016 so there was already evidence against GDF11 then.

Results since that further support GDF11 being a pro-aging factor:

Supraphysiological levels of GDF11 induce striated muscle atrophy

Exogenous GDF11 induces cardiac and skeletal muscle dysfunction and wasting

Supraphysiologic Administration of GDF11 Induces Cachexia in Part by Upregulating GDF15

GDF11 Decreases Pressure Overload–Induced Hypertrophy, but Can Cause Severe Cachexia and Premature Death

GDF11 induces kidney fibrosis, renal cell epithelial-to-mesenchymal transition, and kidney dysfunction and failure

GDF11 expressed in the adult brain negatively regulates hippocampal neurogenesis

I would be extremely careful with increasing the activity of any SMAD2/3-coupled TGFB-like ligands, as aside from muscle loss, they cause fibrosis and cellular senescence across the body. This family of ligands includes TGFB1, activin A (which is a component of the SASP), myostatin, and GDF11. Although GDF15 was thought to fall into this group, this was probably due to TGFB1 contamination of rGDF15, as TGFB1 has activity in the femto(!)molar range.

Follistatin neutralizes some of these (including myostatin, activin A, and GDF11) and follistatin overexpression in mice extends lifespan (17% increase relative to a 900 day control). While elevated circulating follistatin in humans is associated with increased risk of mortality and cardiometabolic disorders, this appears to be a compensatory response as

In addition to being acutely regulated, circulating follistatin is increased in the patients with type 2 diabetes and correlate with markers of insulin resistance such as fasting glucose, glycated hemoglobin, and 2-hour glucose during an oral glucose tolerance test (9). As circulating follistatin is increased during states of energy deprivation such as prolonged fasting (39) and exercise, conditions associated with increased gluconeogenesis, it could be speculated that circulating follistatin acts in negative feedback loop to regulate hepatic gluconeogenesis. Surprisingly, deletion of the (circulating) follistatin 315 isoform in mice results in augmented gene expression of GLUT2, PEPCK, and G6P (48), consequently suggesting that circulating follistatin suppresses gluconeogenesis. excerpt from Circulating Follistatin Is Liver-Derived and Regulated by the Glucagon-to-Insulin Ratio

As myostatin downregulation only suffices to normalize lifespan to the 900 day mark (see Haploinsufficiency of myostatin protects against aging-related declines in muscle function and enhances the longevity of mice), it’s plausible that suppression of multiple TGFB-family members mediates follistatin’s anti-aging effects. In humans, there’s evidence for myostatin suppression promoting longevity, where the hypertrophy-promoting K153R polymorphism is enriched in both Italian and Spanish centenarian cohorts.

Considering that TGFB antagonism extends lifespan in α-Klotho (−/−) mice, it’s tempting to speculate whether a similar role to follistatin is played by circulating α-Klotho, which binds to myostatin as well as its receptors, and can block transcriptional activation by multiple TGFB-family ligands (including myostatin, activin A, GDF11, and TGFB1). See Circulating α-Klotho Counteracts Transforming Growth Factor-β–Induced Sarcopenia

Lastly, looking at the intracellular effectors of TGFB-family signaling, a SMAD3 enhancer variant leads to reduced expression, and is enriched in centenarians. Preprint

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#231

If you want a low-risk way to increase follistatin, you can supplement epicatechin. I’m going to start taking it.

Epicatechin induces mitochondrial biogenesis and muscle regeneration in BMD. It is the only oral compound ever demonstrated to both increase plasma follistatin and decrease plasma myostatin, whose ratio may comprise a future pharmacodynamic biomarker abstract only

Screenshot 2025-01-15 at 8.15.02 PM
Screenshot 2025-01-15 at 8.15.02 PM952×820 58.9 KB

Also, 1mg/kg/day increased circulating follistatin in an Iranian :grimacing: RCT Improvement in Skeletal Muscle Strength and Plasma Levels of Follistatin and Myostatin Induced by an 8-Week Resistance Training and Epicatechin Supplementation in Sarcopenic Older Adults

Another study (Effects of (−)-epicatechin on molecular modulators of skeletal muscle growth and differentiation) found

Treatment for 7 days with Epi yielded a bilateral increase in hand strength of ~7% which was accompanied by a significant increase (49.2 ± 16.6 %) in the ratio of plasma follistatin/myostatin levels (data not shown).

Also interesting to note that dark chocolate contains ~100-200mg epicatechin per oz, and is associated with good health outcomes, despite many chocolates being high in added sugars.

Few studies with mixed results have examined the association between chocolate consumption and mortality. We aimed to examine this association in a US population. A population-based cohort of 91891 participants aged 55 to 74 years was identified. Chocolate consumption was assessed via a food frequency questionnaire. Cox regression was used to estimate risk estimates. After an average follow-up of 13.5 years, 19586 all-cause deaths were documented. Compared with no regular chocolate consumption, the maximally adjusted hazard ratios of all-cause mortality were 0.89 [95% confidence interval (CI) 0.84–0.94], 0.84 (95% CI 0.79–0.90), 0.86 (95% CI 0.81–0.93), and 0.87 (95% CI 0.82–0.93) for >0–0.5 servings/week, >0.5–1 serving/week, >1–2 servings/week, and >2 servings/week, respectively (P trend = 0.009). A somewhat stronger inverse association was observed for mortality from cardiovascular disease and Alzheimer’s disease. A nonlinear dose–response pattern was found for all-cause and cardiovascular mortality (all P nonlinearity < 0.01), with the lowest risk observed at chocolate consumption of 0.7 servings/week and 0.6 servings/week, respectively. The favorable associations with all-cause and cardiovascular mortality were found to be more pronounced in never smokers than in current or former smokers (all P interaction < 0.05). In conclusion, chocolate consumption confers reduced risks of mortality from all causes, cardiovascular disease, and Alzheimer’s disease in this US population.

In this prospective study, calorie-balanced greater consumption of chocolate was inversely associated with lower overall, CVD, heart disease and cancer mortality. The systematic review and meta-analysis provide support for the inverse chocolate-CVD association. Our findings may provide evidence to partially allay concerns regarding adverse health outcomes from low-to-moderate chocolate consumption.

Considering follistatin negatively regulates gluconeogenesis it’s not surprising the follistatin-overexpressing mice show exquisite glucose management.

Glucose tolerance is known to decrease with aging. Here, we used a glucose tolerance test in fasted mice (22 mo old) from each treatment group (Fig. 4E) (39). The average peak glucose concentration was ∼33% lower for TERT and ∼28% lower for FST treatments than for controls. Moreover, blood sugar levels reached baseline at 3 h postadministration in MCMVTERT- and MCMVFST-treated mice, in contrast to ∼8 h for control mice. In addition, the level of glycated hemoglobin (A1C) in treated mice (23 mo old) was 4.5% (TERT) and 4.7% (FST), versus mock (7.9%) or WT (8.8%) (Fig. 4F). TERT and FST treatments were equally effective in blood glucose processing. from New intranasal and injectable gene therapy for healthy life extension

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#232

Yes. Lets see what the ITP finds when epicatechin is tested on wild type mice.

Have you a good source for epicatechin?

1 Like
#233

I used Nootropics Depot.

#234

Interesting to note the following was written about Jeanne Calment (the oldest verified person ever):

She showed herself more than once capable of absorbing considerable quantities of chocolate: more than a kilo per week

Asking ChatGPT about the amount of epicatechin she would have consumed at 1kg chocolate per week (dark chocolate consumption would give the higher estimate)

If the person consumed a mix of dark and milk chocolate, the value would fall between 75–500 mg per week , depending on the proportions. For a French person in the 20th century, it’s plausible they ate more dark chocolate, aligning with cultural preferences for high-cocoa-content products.

Mine just arrived today and I had 50mg, which is tasteless in water. Thinking I’ll run 50mg 2x/day, which how much they used in the trial with BMD patients.

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#235

This is a interesting talk with performance coach Alex Kikel, maybe a bit “over the top” for some, that’s why I think this is the right topic to post this :wink:
I have been following Alex Kikel for a long time and I have tried some of his protocols in the past with succes ( injectable carnitine and glutathion). Things that are mentioned:

SLU-PP-332 (SLOOP), SS31, MOTS-C
Methylene blue
Modafinil
GLP-1 Fat Loss Peptides Tirzepatide & Retatrutide
Myostat inhibitors
Cerebrolysin
Naltrexon, DADA
Rapamycin use in the weekend for athletes
Urolinth A, injectable Glutathion with Taurine

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#236

Thanks. Interesting discussion. Alex Kikel is a wild man but smart. He is the bleeding edge. I wouldn’t take his word alone on anything. https://theprepcoach.com/

I was surprised to hear for the first time about a danger in methylene blue related to kidney function. He mentioned a genetic trait that is rare.

He also said…methylene blue improves brain ability to utilize all fuels for higher energy production. This is consistent with my experience (brain fog killer).

10mg dose for avoiding getting sick (traveling)
30-50mg is a typical daily dose for most people for energy boosting.

I’ve never used more than 15mg in a day. And never everyday. Perhaps there’s more upside but on the other hand methylene blue is a synthetic dye so I don’t want to be stupid.

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#237

May I ask about your positive experience of injected carnitine?.

#238

I use 800mg injectable carnitine when I do a long trail run (half marathon), I do this every 2 weeks.
I have the impression that this makes the effort a little less hard. Most of the time I combine the injection with 600mg glutathione (Tationil , an Italian product)

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#239

If one is of Mediterranean or African decent, there is an increased likelihood of having a trait that would increase the risk of MB. From what I’ve read, it’s most likely to occur in men, but being one to have some Mediterranean in me, I took a blood test to confirm I was in the clear before starting.

From google AI

  • G6PD deficiency is inherited and is most common in African-American men and men of Middle Eastern or Mediterranean descent.

  • It’s usually passed on to male children from their mother, even if she probably had no symptoms herself.

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#240

Thanks for mentioning that, I didn’t realize that was the issue. I was tested before chelation therapy and am good. MB works well for me and I’ve had no trouble.

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#241

I do occasional sub-perceptible microdoses of LSD, as I mentioned in another thread, and they’ve really boosted my qol. I’m hoping there’s some neurogenesis happening. Plus, they’re great for a little euphoria and make “forest bathing” a bit more “magical” :grin: :grin:

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