SS-31 protocols?

[Skidude]

I feel ya. I've been on 5mg daily for 11 days. Starting Mots-c on day 14. 5mg daily with two days off (3/2). Ss-31 will probably always be part of the rotation since I have felt some energy and focus gains.

I may have plagiarized your "pep in the step" when writing.. lol

 

[Calm Logic]

Elamipretide (SS-31), a synthetic tetrapeptide, is being investigated for its potential to help individuals with damaged mitochondria . SS-31 is designed to selectively target mitochondria, aiming to restore their function, particularly in conditions like mitochondrial diseases and aging.

Thanks again. I just started reading about SS-31 a week ago. I didn't know that Elamipretide was the name for it, or that its peptide class is tetrapeptide.

 

[Calm Logic]

Trial dosages are in the range of 20mg (low dose trials)-40mg/day sub-q. Based on that, there's no reason to think less than 1mg/day is going to do literally anything besides give your an occasional bruise from the injection. Here's an example for dry eye age related macular dysfunction. https://clinicaltrials.gov/study/NCT06373731?intr=Elamipretide&rank=4

This is a peptide where human clinical trial data actually exists. 500mcg is pointless.

Similarly, from another study by the same company, SS-31 was well-tolerated at 40mg/day (though not effective for a rare disorder):

Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial - PMC

Primary mitochondrial myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely affecting physical function, exercise capacity, and quality of life (QoL). Current PMM standards of care ...

pmc.ncbi.nlm.nih.gov

2023 Jul 18

After screening, eligible participants were randomized 1:1 to receive either 24 weeks of elamipretide [SS-31] at a dose of 40 mg/d or placebo subcutaneously...

Subcutaneous elamipretide treatment did not improve outcomes in the 6MWT [Six-Minute Walk Test] and PMMSA TFS [Primary Mitochondrial Myopathy Symptom Assessment Total Fatigue Score] in patients with PMM [primary mitochondrial myopathy]. However, this phase-3 study demonstrated that subcutaneous elamipretide [SS-31] is well-tolerated .

 

[Calm Logic]

From a small study (PDF) using rats:

"Our data show the potential of SS-31 as a novel therapeutic in cardiac arrest"

"Previous studies tested SS-31 using different dosages invarious diseases [ 3 ] and 0.05mg/kg/h is a commonly used dosage for continuous administration with consistent effectiveness"

"Mitochondrial dysfunction is believed to play an important role for the pathogenesis of cardiac arrest."

"The wide spectrum of protective action makes SS-31 a promising therapeutic agent in CA [cardiac arrest], where multiple organs are affected."

 

[FlowerFairy]

I tried MOTSc for about two weeks but didn't have any increased energy or anything. Then I realized I should have started with SS-31 first to prime my system so to speak so I stopped it LOL..... That's around the same time of my Tirz stall aka its never really worked for me.

So I came up with the plan to do a cycle of NAD & AOD between cycling off the Tirz. I do notice increased energy with the NAD+ as well, I was impressed since I've never had consistent responses from Sema or TIrz, FINALLY something my body is working with.

I'll start Reta January first, as long as I make it that long. Then I'll drop the AOD mid January and start the SS31, followed by the MOTSc....... I'll need a calendar to keep these things straight lol

I was told that you use as-31 first, then MOTS-C, because the first one heals and optimizes, but I don’t know if it’s true.

 

[Skidude]

I think most are quoting Dr. Seeds protocol, although I have not been able to confirm, it is certainly my motivating reason to buy into ss-31 then mots.

From his book:

William A. Seeds, MD is a board-certified surgeon practicing medicine for over 30 years. He is Founder and Chairman of the International Peptide Society, Faculty Developer and Lecturer of the A4M Peptide Certification Program, and a leading peptide therapy researcher. He is Chief of Surgery and Orthopedic Residency Site Director for University Hospital, Conneaut, and Medical Director of Orthopedic Rehab and Sports Medicine at the Spire Institute, a USA Olympic training site. Dr. Seeds has been honored at the NFL Hall of Fame for his medical expertise and in treating professional athletes, and serves as Professional Medical Consultant for the NHL, MBL,NBA, and NBC’s Dancing with The Stars.

Home - William Seeds Site

HERE is one of his podcast interviews, many more links on youtube.

HERE is another example from a random user I found:

It’s a matter of mitochondrial genomics and their ability to self replicate (only other self replicating organelle I can think of are peroxisomes in animals).

Remember: The mitochondrial membrane have the proteins responsible for the cell to produce “energy” and “breathe” for the cell — the electron transport system. So a partially denatured and damaged membrane of mitochondria (phospholipid cardiolipin) make it harder for the cell to do its normal function, producing proteins, etc…leading to be harder for tissues and organs to function properly and the body being tired and lack ability to properly function.

Mitochondria are self replicating. If one has mitochondrial breakdown of membranes due to ROS — reactive oxygen species — free radicals…at any point mutations (or others) in the mitochondrial genome is likely to reproduce/self-replicate mitochondria with those same mutations (F1 generation).

Furthermore, like any other genome or organism — remember though it is the mitochondria is an organelle — and, it is subject to both epigenetics and pleiotopy. If the mitochondria are exposed to ROS, these ROS have an effect on gene expression resulting in possible mitochondria expressing genes (phenotypes) that underwent mutation. Pleiotropy — if an affected mitochondria results in mutations prior to self replication, and if gene is pleiotropic (but consider all genes are pleiotropic to some degree) that has expression of that mutation will result in many phenotypic changes that are deleterious in the normal functioning of that mitochondria and hence likely the entire cell.

Therefore, healing properties of SS-31 will have a greater effect on mitochondrial function within cells and (theoretically) other peptides will be more effectual in helping the body.

This an oversimplified description of genetics of mitochondria or the cell itself.

Main point— SS31 or Humarin (HGN) should come before MOTS-C which directly stimulates the present mitochondria (at time of use ) to performing better.

I mentioned peroxisomes notable function is to “neutralize” reactive oxygen species in the cell or detox the cell of free radicals. Also they are involved in metabolism (catabolism) of fatty acids in the cells. Due to the structure of fatty acids— they are hydrogen rich — the hydrogen density exposes them to reactive oxygen species. I am not aware of any peptide that helps peroxisomes function better.

 

[Skidude]

I just read the Peptide Protocols book and there is no mention of SS-31, so it must be something that either came up at a later date (after 2020) or that is being attributed to him inaccurately.

It does seem to be supported by his assessment of cell protection/optimization theory, in my layman's understanding.

Full disclosure, I had to google a lot of terms...

 

[Calm Logic]

From Goodkitty at Peppys:

For the SS31 and the MOTS C - since they are more mitochondrial - I didn’t’ expect to have any “feels” but hope to see improvements on followup mitochondrial/telomere/aging testing when I have it redone.

So with that perspective, I found this:

Telomeres and Mitochondrial Function - PMC

pmc.ncbi.nlm.nih.gov

A new study provides insight into aging and age-related diseases by linking telomere dysfunction to a decline in mitochondrial number and function.

Telomeres and Mitochondrial Metabolism: Implications for Cellular Senescence and Age-related Diseases - PMC

Cellular senescence is an irreversible cell arrest process, which is determined by a variety of complicated mechanisms, including telomere attrition, mitochondrial dysfunction, metabolic disorders, loss of protein homeostasis, epigenetic changes, ...

pmc.ncbi.nlm.nih.gov

Cellular senescence is an irreversible cell arrest process, which is determined by a variety of complicated mechanisms, including telomere attrition, mitochondrial dysfunction, metabolic disorders, loss of protein homeostasis, epigenetic changes, etc. Cellular senescence is causally related to the occurrence and development of age-related disease...More and more evidences have shown that there is mutual crosstalk between telomeres and mitochondrial metabolism in the process of cellular senescence.

Playing with Google Gemini regarding oral supplements vs SS-31:

While many oral supplements for mitochondrial health aim to support overall mitochondrial function, very few are specifically designed to target the inner mitochondrial membrane in the same way that SS-31 does.

Here's a breakdown of why and some potential exceptions or related concepts:

Why Direct Targeting is Difficult for Oral Supplements:

Absorption and Distribution: Oral supplements go through the digestive system, are absorbed into the bloodstream, and then distributed throughout the body. Achieving a high concentration specifically within the inner mitochondrial membrane from an oral dose is a significant challenge.

Cellular Uptake: Even if a supplement reaches cells, it needs specific mechanisms to cross the cell membrane and then the outer and inner mitochondrial membranes.

Targeting Mechanisms: SS-31's effectiveness in targeting the inner mitochondrial membrane relies on its specific affinity for cardiolipin, a unique phospholipid found almost exclusively in that location. Most oral supplements lack such a precise targeting mechanism.

However, some oral supplements or their components may indirectly benefit or interact with the inner mitochondrial membrane:

Antioxidants: Certain antioxidants like CoQ10 (ubiquinol) and alpha-lipoic acid can accumulate within mitochondria to some extent and help reduce oxidative stress in both the inner and outer membranes, as well as the matrix. While they don't have a specific targeting mechanism like SS-31, their lipophilic nature allows them to integrate into mitochondrial membranes.

Phospholipid Precursors: Some supplements contain phospholipids like phosphatidylcholine or precursors to cardiolipin . While not directly targeted, providing the building blocks for mitochondrial membranes can support their structure and function, including the inner membrane.

MitoQ: This is a mitochondria-targeted antioxidant that combines ubiquinone (a form of CoQ10) with a lipophilic triphenylphosphonium (TPP+) cation. The TPP+ helps it to be taken up by mitochondria due to the negative charge of the mitochondrial membrane potential. While MitoQ has shown promise, it's not always available as a standard oral supplement and its targeting mechanism isn't solely specific to the inner membrane, but rather the entire mitochondrial matrix.

Urolithin A: This postbiotic metabolite can promote mitophagy, the selective removal of damaged mitochondria, which indirectly supports the health of the remaining mitochondria, including their inner membranes.

In summary:

While many oral supplements provide nutrients that are crucial for overall mitochondrial health and can exert beneficial effects within the mitochondria (including the inner membrane), they generally lack the specific cardiolipin-targeting mechanism of SS-31. Some antioxidants and phospholipid precursors in oral supplements can integrate into or support the inner mitochondrial membrane, but their action is less directly targeted compared to compounds like SS-31 or MitoQ.

The development of truly targeted oral supplements for the inner mitochondrial membrane remains an area of ongoing research.

Peptides with Potential Telomere-Related Effects (Primarily Research):

TA-65: While often available orally, TA-65 is a purified small molecule derived from Astragalus membranaceus that has shown some evidence of activating telomerase, the enzyme that can lengthen telomeres. There have been injectable formulations used in research settings, but it's not a widely available injectable supplement for the general public.

Epitalon (Ala-Glu-Asp-Gly): This synthetic tetrapeptide is a more well-known research peptide with potential anti-aging effects. Studies have suggested it can increase telomerase activity and lengthen telomeres in some cell types and animal models. It is available through some specialized pharmacies and research suppliers as an injectable, but its widespread use and regulatory status vary significantly. Human clinical trial data on its efficacy and safety for telomere lengthening is still limited.

MOTS-c (Mitochondria-Derived Peptide): While primarily known for its role in metabolic regulation and exercise mimicry, MOTS-c has shown some potential links to cellular longevity and mitochondrial health. Given the close relationship between mitochondrial dysfunction and telomere shortening, supporting mitochondrial health through MOTS-c might indirectly benefit telomeres. Injectable forms are mainly used in research.

SS-31 (Elamipretide): As we've discussed, SS-31 targets the inner mitochondrial membrane and reduces oxidative stress. While its primary mechanism isn't direct telomere lengthening, its potent antioxidant effects within mitochondria could help protect against oxidative damage that contributes to telomere shortening. Injectable formulations are used in research and some clinical trials for other indications.

Other Injectable Considerations (Less Direct Telomere Focus):

Certain Antioxidants (e.g., Glutathione, Vitamin C): While available in injectable forms, their primary role is to combat oxidative stress. By reducing cellular damage, they might indirectly help preserve telomere length, but they don't directly target telomeres.

Growth Hormone (GH) and Growth Hormone-Releasing Peptides (GHRPs): These can have various effects on cellular function and might influence aging processes, but their direct impact on telomere length is complex and not well-established as a primary benefit for preventing telomere shortening.

TA-65: While often available orally, TA-65 is a purified small molecule derived from Astragalus membranaceus that has shown some evidence of activating telomerase, the enzyme that can lengthen telomeres. There have been injectable formulations used in research settings, but it's not a widely available injectable supplement for the general public.

Epitalon (Ala-Glu-Asp-Gly): This synthetic tetrapeptide is a more well-known research peptide with potential anti-aging effects. Studies have suggested it can increase telomerase activity and lengthen telomeres in some cell types and animal models. It is available through some specialized pharmacies and research suppliers as an injectable, but its widespread use and regulatory status vary significantly. Human clinical trial data on its efficacy and safety for telomere lengthening is still limited.

MOTS-c (Mitochondria-Derived Peptide): While primarily known for its role in metabolic regulation and exercise mimicry, MOTS-c has shown some potential links to cellular longevity and mitochondrial health. Given the close relationship between mitochondrial dysfunction and telomere shortening, supporting mitochondrial health through MOTS-c might indirectly benefit telomeres. Injectable forms are mainly used in research.

SS-31 (Elamipretide): As we've discussed, SS-31 targets the inner mitochondrial membrane and reduces oxidative stress. While its primary mechanism isn't direct telomere lengthening, its potent antioxidant effects within mitochondria could help protect against oxidative damage that contributes to telomere shortening. Injectable formulations are used in research and some clinical trials for other indications.

Other Injectable Considerations (Less Direct Telomere Focus):

Certain Antioxidants (e.g., Glutathione, Vitamin C): While available in injectable forms, their primary role is to combat oxidative stress. By reducing cellular damage, they might indirectly help preserve telomere length, but they don't directly target telomeres.

Growth Hormone (GH) and Growth Hormone-Releasing Peptides (GHRPs): These can have various effects on cellular function and might influence aging processes, but their direct impact on telomere length is complex and not well-established as a primary benefit for preventing telomere shortening.

 

[Skidude]

The premise, as I understand it, of Seeds peptide book is homeostasis- the ability of the body to fix itself (my very basic description).

The relationship of cells and how they affect us as a whole.

He discusses Senescence in detail as well as telomere

From his book:

Cell Senescence Cell senescence was first discovered in the 1960s by Hayflick and Moorhead, who observed a number of cells that simply stopped dividing— they neither grew and divided nor progressed to cell death—these cells were arrested. This phenomenon changed our understanding of the cell cycle. Hayflick and Moorhead went on to define cell senescence as an indication of a cell’s biological clock; they called it the Hayflick limit. At the time, the cell arrest of senescence was attributed to a progressive shortening of telomeres with each cell division. They understood this telomere erosion to be part of a physiological response to prevent genomic instability and DNA damage. Now we know that cell senescence is much more complicated.

So how and why does senescence occur? Senescence can be triggered by various mechanisms, through multiple pathways: Gradual erosion of telomeres, triggering a DNA damage response in the genome of the mitochondria Chronic physiological stress, including bad diet, lack of exercise, and stubborn insult to glucose metabolism. Downstream of senescence brought on by physiological stress, you will find oxidative stress, endoplasmic reticulum stress (resulting in unfolded protein response or UPR),mitochondrial stress (cytoplasmic chromatin fragments, or CCFs), and interferon-related responses. Acute injury or trauma to any area of the brain or body (anything from osteoarthritis in a knee to a TBI) As a result of anti-cancer treatments (radiation and chemotherapy) that purposely bring cell senescent onset; this is often referred to as therapyinduced senescence. Finally, senescence is the result of a systemic proinflammatory state, which has driven the immune system into hyper mode, degrading its ability to maintain homeostasis cellular protection. Essentially, any of these senescence inducers are a form of stress on the cell and its systems. Yes, the cell requires stress to nudge it into its cell cycle. However, when any one or more of these stressors overwhelms the cell—in either their degree or their chronic-ness—the cell’s ability to adapt becomes undermined. Cellular senescence is even more dangerous because it not only affects an individual cell, but it also affects nearby and distant tissue through chronic inflammatory response, reactive oxygen species, and insufficient apoptosis. The bottom line is that the characteristics of the senescent cell—in particular its secretory phenotype—diminish its resistance to diseasecausing stressors and cause stem and parenchymal cell dysfunction. (Indeed, stem cells are particularly vulnerable to damage from SASP because of the harmful effect on their microenvironment, or niche.

 

[Peloma]

2 days ago, I added methylene blue to the stack. I know... I fell victim to the hype. Let me tell you, it's legit! The methylene blue gives an extra boost to my energy, and pairs really well with my SS-31. I have more focus and energy this morning than on SS-31 alone, and knowing that the SS-31 is in the background repairing mitochondria while the blue moves electrons to needed parts in my cells is a great feeling.

Downside was with sleep... didn't get much. I'm sure it will adjust as I acclimate.

 

[Calm Logic]

Cool. I know my local compounding pharmacist is promoting methylene blue like crazy, so I guess I will try it now.

Regarding Dr. Seeds and cell signaling, I see this is what he says about GLP-1s:

Rewriting Metabolic Destiny: GLP-1R Agonists as the Natural Key to Cellular Efficiency and Epigenetic Renewal | Integrative Healthcare Symposium

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), mimicking our body's natural incretin hormones, have transformed metabolic disorder management. Beyond their known efficacy in blood sugar control and weight loss, emerging research...

www.ihsymposium.com

Key takeaway points include:

– GLP-1 receptor agonists (GLP-1 RAs) have multifaceted effects beyond glucose control and weight loss, influencing multiple cellular pathways crucial for metabolic health and longevity.

– GLP-1 RAs modulate key signaling pathways such as insulin signaling, mTOR, AMPK, Nrf-2, sirtuin activity, and NAD⁺ metabolism, leading to enhanced mitochondrial function, energy balance, and reduced oxidative stress.

– GLP-1 RAs exhibit anti-inflammatory and senomodulatory properties, impacting immune cell polarization, promoting positive epigenetic modifications, and influencing cellular senescence, which may reverse harmful changes associated with chronic metabolic diseases, aging, and cancer.

 

[Peloma]

Cool. I know my local compounding pharmacist is promoting methylene blue like crazy, so I guess I will try it now.

Regarding Dr. Seeds and cell signaling, I see this is what he says about GLP-1s:

Let me know when you do. We can compare notes. I've taken 20 drops (.5mg/drop = 10mg) Sunday, yesterday morning and this morning. Last night I dropped 40 drops (20mg), and I really felt it, but that's also probably why I couldn't sleep. Tonight it will be 20 drops again to total my daily dose at 20mg.

 

[Calm Logic]

When I was watching The Pitt, they were also using methylene blue for some ER thing

 

[Peloma]

When I was watching The Pitt , they were also using methylene blue for some ER thing

I missed that one. I enjoyed that show. I may have to go back and check it out.

 

[Calm Logic]

Let me know when you do. We can compare notes. I've taken 20 drops (.5mg/drop = 10mg) Sunday, yesterday morning and this morning. Last night I dropped 40 drops (20mg), and I really felt it, but that's also probably why I couldn't sleep. Tonight it will be 20 drops again to total my daily dose at 20mg.

What brand is yours?

 

[Peloma]

Biopharm straight off Amazon. It was well priced abd tested. I may go with the pills going forward because this liquid tastes like shit.

 

[Calm Logic]

You could always mix it with tuna juice like people do for medicating their cats

Methylene blue is known to have a bitter or unpleasant taste that some describe as similar to dirt water. Here are a few things you could try mixing with it to potentially help improve the taste:

Sweeteners: Adding a small amount of a natural sweetener like honey or a sugar substitute such as stevia or erythritol might mask the bitterness.

Juices: Mixing methylene blue with a small amount of a strongly flavored juice, such as cranberry or grape juice, could help to cover up the taste.

Flavored Liquids: Consider using a flavored electrolyte drink or a sugar-free flavored water to dilute the methylene blue.

 

[Skidude]

Take caution if combining the Methylene Blue with Tesofensine or other SSRIs-

Tesofensine is a triple monoamine reuptake inhibitor, meaning it affects dopamine, serotonin, and norepinephrine. It is being studied as a potential treatment for obesity and other conditions, and has shown some promising results in reducing weight. However, its use with MAOIs (monoamine oxidase inhibitors) is not well-studied, and there are potential risks involved.

Methylene blue is a monoamine oxidase inhibitor (and, if infused intravenously at doses exceeding 5 mg/kg, may result in serotonin syndrome if combined with any selective serotonin reuptake inhibitors (SSRIs) or other serotonergic drugs (e.g., duloxetine, sibutramine, venlafaxine, clomipramine, imipramine).

 

[Peloma]

Take caution if combining the Methylene Blue with Tesofensine or other SSRIs-

Tesofensine is a triple monoamine reuptake inhibitor, meaning it affects dopamine, serotonin, and norepinephrine. It is being studied as a potential treatment for obesity and other conditions, and has shown some promising results in reducing weight. However, its use with MAOIs (monoamine oxidase inhibitors) is not well-studied, and there are potential risks involved.

Methylene blue is a monoamine oxidase inhibitor (and, if infused intravenously at doses exceeding 5 mg/kg, may result in serotonin syndrome if combined with any selective serotonin reuptake inhibitors (SSRIs) or other serotonergic drugs (e.g., duloxetine , sibutramine , venlafaxine , clomipramine , imipramine ).

I read that, and it kept me from my dose of selank. I did just bang 700mg of Semax. Let's see how well they play together.

 

[Skidude]

I have not read up too much on serotonin syndrome, but it sounds like no fun from what I have read.