Interleukin-11 inhibition slows aging, results in 25% Lifespan Increase

[Curious]

I hope someone will have the oppertunity to ask Stuart about the effect of IL-11 on epigenetic clocks.

[ng0rge]

“Viewed from a great distance, Earth appears as
a pale blue dot(1). It is only at a closer scale that
interesting details emerge, such as mountains
and cities.”

Love it…especially the (1) reference to Carl Sagan…that’s like shouting “We ARE Scientists! (COSMIC!)”

[WJ_PhD]

I found the commentary by Miller to be very insightful. I especially liked this quote towards the end

" This study also provides a model, and a spur, for moving beyond the broad, widely accepted, but non-specific, consensus that the deleterious consequences of ageing reflect ‘inflammation’. Or, similarly, that they reflect the accumulation of ‘senescent’ cells (cells that can no longer divide) or ‘epigenetic changes’ as estimated by patterns of methyl-group modifi-cations throughout the genome. It has become popular in the study of biological ageing to reify these and other vaguely defined concepts as ‘hallmarks of ageing’. Such pseudo-official lists of ‘hallmarks’ represent a kind of brand-ing that can often block critical consideration, specification and prioritization of each hall-mark lucky enough to achieve this badge of honour."

[Walter_Brown]

I’m loving my galantamine 4mg with Metformin 500mg stack. It reproduces success in disrupting sarcopenia. I learnt about the cholinergic anti-inflammatory pathway.

https://www.sciencedirect.com/science/article/pii/S0149763416305723

[desertshores]

I hadn’t seen that association before, though I am a fan of galantamine as it is one of the few supplements that I take that has subjective results.

“Galantamine has been reported to significantly reduce all-cause mortality and improve functionality in patients with AD”

I am not currently a fan of metformin for many reasons, one of which is:
“Metformin Blunts Muscle Hypertrophy in Response to Resistance Training in Older Adults”

So, I am surprised it has any effect on reducing sarcopenia.

It may be effective because of its anti-inflammatory properties.

Based on one study, I don’t think the evidence is strong.

[RapAdmin]

Investors seem to be betting $20 Million that it does (and I suspect they have more evidence than just 1 study): A combinação de medicamentos da Rejuvenate Biomed (metformina e galantamina) mostra-se promissora na sarcopenia no ensaio de Fase 1b

[desertshores]

On the other hand, since the main aim of metformin is glucose control, maybe other combos of glucose-controlling drugs + galantamine might do just as well or better.
More studies are needed.
Based on one ongoing trial I am not convinced.

[Walter_Brown]

I’ve only been doing 4mg in the morning. Am considering adding 4mg at night too…Does it make falling asleep easier or more difficult? How close to bed time has been ideal for you?

[desertshores]

I don’t like taking it too close to bedtime because I feel it interferes with my sleep quality.
The half-life of galantamine is ~7hrs +, so I don’t think it has to be taken more than once per day as the 5 half-life clearance would be about 35 hours.

[vamin]

Sorry if I missed it, what’s the connection between galantamine and IL-11?

[desertshores]

@vamin

what’s the connection between galantamine and IL-11

“Some studies suggest that the anti-inflammatory effects of galantamine may influence the levels and activity of various cytokines, including IL-11. However, the specific interaction between galantamine and IL-11 is not extensively studied.
It is hypothesized that galantamine’s modulation of the immune response could potentially affect IL-11 production or signaling, contributing to its overall anti-inflammatory effects.”

[Luminary]

For my post earlier, I totally missed the fact that everything that I was looking for was readily available. The dose in the nature study was stated here:

“Mice were either aged naturally (untreated) or given either X203 or an IgG control antibody (40 mg kg−1, every 3 weeks) starting from 75 weeks of age for a duration of 25 weeks”

From chatgpt:
"Given Data:
Mice Dose (NOAEL): 40 mg/kg
Mice Km Factor: 12.3
Human Km Factor: 37

Using Km Factor Method

The formula for converting the dose is (from this FDA conversion paper):

HED (mg/kg) = Animal dose (mg/kg) × (Animal Km / Human Km)

Substitute the values:

HED (mg/kg) = 40 × (12.3 / 37)

Calculate the Km ratio:

12.3 / 37 ≈ 0.332

Now, multiply by the dose:

HED (mg/kg) = 40 × 0.332 ≈ 13.28
"
Also, chatgpt says that it is likely an IgG antibody which has a half life of 21-28 days. So, the 13.28 mg/kg human dose is similar to that from the lassen study (~600-1200 mg):
A Novel Interleukin-11 Receptor Antibody, LASN01 Is Well Tolerated and Demonstrates Target Engagement in Phase 1 | European Respiratory Society

That makes the 100 mcg dose for the X203 from here seem really low:
https://www.biocompare.com/9776-Antibodies/18635225-Research-Grade-Anti-Human-IL11-Antibody-X203/?pda=9776|18635225_0_0||1|x203

[RapAdmin]

anti-aging antibodies?

[desertshores]

What I can find about IL-11 inhibitors;

The query:

“Find all known or theoretical suppressors of IL11 interleukin 11, peptides, drugs, chemicals or supplements.”

In the interest of space, I did not include the complete results.

If you want more complete details you can do a query yourself.

Chat GPT:
Known Suppressors
Pharmaceutical Agents:

TGF-β Inhibitors: IL-11 is often induced by transforming growth factor-beta (TGF-β), so inhibiting TGF-β can indirectly reduce IL-11 levels. Examples include small molecule inhibitors like SB431542 and LY2157299.

Anti-IL-11 Antibodies: Specific monoclonal antibodies targeting IL-11 or its receptor could be developed to neutralize its activity. Research into these therapies is ongoing.
JAK Inhibitors: Since IL-11 signaling involves Janus kinase (JAK) pathways, JAK inhibitors like Tofacitinib and Baricitinib may reduce IL-11 mediated effects indirectly.

Biological Agents:

IL-11 Antagonists: There are potential peptides or proteins designed to antagonize IL-11, although these are primarily in experimental stages.

Anti-Fibrotic Agents:

Nintedanib and Pirfenidone: These are used in idiopathic pulmonary fibrosis and may impact IL-11 indirectly through their effects on fibrotic processes.

https://asklongevitygpt.com:

Known Suppressors of IL-11
Tocilizumab:
Type: Monoclonal antibody
Mechanism: Tocilizumab targets the IL-6 receptor, which can indirectly suppress IL-11 signaling pathways due to the interconnected nature of cytokine signaling networks.
Use: Approved for the treatment of rheumatoid arthritis and other inflammatory conditions.

Ruxolitinib:
Type: JAK1/2 inhibitor
Mechanism: Ruxolitinib inhibits the Janus kinase (JAK) pathway, which is involved in the signaling of various cytokines, including IL-11.
Use: Approved for the treatment of myelofibrosis and polycythemia vera.
Statins:
Type: Cholesterol-lowering drugs
Mechanism: Statins have been shown to have anti-inflammatory effects, including the suppression of various cytokines such as IL-11. They inhibit the mevalonate pathway, which can reduce the production of inflammatory mediators.
Use: Used to lower cholesterol levels and reduce the risk of cardiovascular disease.

claude.ai:
Natural Compounds:

Curcumin - shown to suppress IL-11 expression in some studies
Resveratrol - may modulate IL-11 signaling

I did not include redundant results from other AI sites.

Also from the queries:

"Synthetic Peptides:
Mechanism: Synthetic peptides can be engineered to mimic natural inhibitors of IL-11 or disrupt its interaction with its receptor. These peptides can be designed to have high affinity and specificity for IL-11 or its receptor.

Research Status: Early-stage research with promising results in preclinical studies. Further research is needed to confirm their efficacy and safety in clinical settings."

I hope some peptides are found soon as they seem relatively safe to use.

[DeStrider]

5 Supplements To Inhibit IL-11

[DeStrider]

Where can I buy Galantamine? I haven’t been able to track down a good source and Jagdish won’t sell it. Thanks!

(Update: Bought it from Maulik.)

[desertshores]

@DeStrider

Where can I buy Galantamine?

Maulik Parekh maulik7@gmail.com
Galamer 4 mg - 40$ / 100 pills
Shipping extra

I received the galantamine in less than three weeks.
He is currently my go-to guy for every med/supplement from India.

I no longer use Jagdish even though he was my original supplier of things from India because he is unwilling to ship some common items that are even over the counter in the U.S. and other low-level meds such as trazodone.

[RapAdmin]

@desertshores

Curcumin - shown to suppress IL-11 expression in some studies

“Turmeric or curcumin, green tea extract, Garcinia cambogia, black cohosh, red yeast rice, and ashwagandha are the most frequently reported hepatoxic botanicals…”

Source: x.com

Journal article:

Estimated Exposure to 6 Potentially Hepatotoxic Botanicals in US Adults

[desertshores]

@RapAdmin

“Turmeric or curcumin, green tea extract, Garcinia cambogia, black cohosh, red yeast rice, and ashwagandha are the most frequently reported hepatoxic botanicals…”

Millions of people take these supplements without coming to harm.
There are always those who think they need to take more than the recommended dose. If the supplement bottle says “Take one daily”, they may take a far greater amount.
Also, this observational study does not take into account confounding variables.

Most people in the forum have regular blood work done to monitor the effects of supplements and medications.

“The risk of liver injury does not appear to relate to Curcuma longa (turmeric) when consumed in typical dietary amounts as a food,”

Turmeric and green tea among health supplements putting people in hospital

[Cohen]

This study showed that lutein protected against Ang II-mediated deleterious cardiac remodeling by inhibiting the IL-11 protein. In vitro, lutein treatment reduced oxidative stress, proliferation, migration, and phenotypic transformation in cultured neonatal CFs. In vivo, lutein prevented cardiac functional deficits and reduced cardiac fibrosis in Ang II-induced model mice. We further discovered that IL-11 overexpression prevented the protective effects of lutein against Ang II-induced pathological cardiac remodeling. Importantly, lutein suppressed Ang II-induced IL-11 expression by inhibiting the activity and expression of c-Jun/Jun-B.

Accumulating evidence has suggested that the pathological remodeling response is coordinated with oxidative stress, inflammation, apoptosis and numerous signaling pathways. Jinrui Dong’s study showed that IL-11 activity causes hepatocyte death through NOX4-derived ROS, activation of ERK, JNK and caspase-3, impaired mitochondrial function and reduced fatty acid oxidation [51].

Stuart Cook and colleagues showed that the upregulation of cytokine IL-11 was the dominant transcriptional response to Ang II and TGF-β1 exposure. Jinrui Dong’s study showed that IL-11 activity causes hepatocyte death through NOX4-derived ROS, activation of ERK, JNK and caspase-3, impaired mitochondrial function and reduced fatty acid oxidation [51]. Anissa A. Widjaja’s study discovered an unexpected proinflammatory role for IL-11 in the liver [49]. In line with the above findings, our current data demonstrated that lutein markedly suppressed Ang II-induced oxidative stress, inflammation and apoptosis in CFs by inhibiting the expression of IL-11. These results revealed inhibiting lutein is a potential therapeutic strategy to treat cardiac fibrosis.

Lutein attenuates angiotensin II- induced cardiac remodeling by inhibiting...